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External Advisory Board Visit Immunology Institute Icahn School of Medicine at Mount Sinai May 29th 2014

Immunology Institute

Icahn School of Medicine at Mount Sinai

This document is dedicated to the memory of our friend and colleague Lloyd Mayer, MD (1952-2013), whose vision, intelligence, dedication, and collegiality, were essential for the development of immunology at Mount Sinai.

Contents ! Immunology Institute Faculty ! Introduction ! Programs • Mucosal Immunology • Allergy • Immunodeficiency • Human Immune Monitoring Center • Immunotherapy ! Education ! Appendixes • Immunology Institute Faculty Publications • Fundamentals in Immunology Schedule • Immunology Seminar Series • Immunotherapy studies • Biosketches ! Credits

Immunology Institute Faculty

Alexandropoulos, Konstantina Berin, Cecilia Bhardwaj, Nina Blander, Julie Bona, Constantin Brody, Joshua Brown, Brian Burakoff, Steven Busse, Paula Cerutti, Andrea Chen, Benjamin Chen, Shu-hsia Cho, Judy Clemente, Jose Colombel, Jean-Fredric

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Cortes, Patricia Cunningham-Rundles, Charlotte Dahan, Stephanie Davies, Terry Esplugues, Enric Faith, Jeremiah Furtado, Glaucia Gnjatic, Sacha Gulko, Percio Guttman-Yassky, Emma Heeger, Peter Li, Xiu-Min Lira, Sergio Masilamani, Madhan Mehandru, Saurabh

Merad, Miriam Moran, Thomas Murphy, Barbara Ochando, Jody Sampson, Hugh Sealfon, Stuart Sikora, Andrew Ting, Adrian Tomer, Yaron Xiong, Huabao Yeretssian, Garabet Zhou, Lan Zier, Karen

The Immunology Institute of Mount Sinai School of Medicine was established in February of 2007. The main mission of the Immunology Institute is to foster research, collaboration, and education in immunology. The team The Institute is led by Sergio Lira and is home to 42 basic scientists and clinicians (Appendix V). The programs Immunology Institute investigators study the physiology and pathophysiology of immune cells with a special emphasis on the mechanisms of disease pathogenesis, and development of therapeutic interventions. Our main programmatic areas are Mucosal Immunology, Immunodeficiencies, Food Allergy, Immunomonitoring and Immunotherapy. Our basic and clinical researchers collaborate extensively. We have unique patient populations who give us an advantage in terms of translational science. Where we do not have direct access to human samples, animal models of disease are created. This melding of patient populations with animal models and multiple approaches to study mechanisms is unique and serves to distinguish the Immunology Institute from other Immunology programs around the country. In our institute, faculty with interest in diverse aspects of the immune system work together to achieve excellence in research, mentoring, and training.

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Mucosal Immunology Mount Sinai and IBD have been synonymous since 1932 when the initial description of Crohn’s disease was made at Mount Sinai. There is a strong base of clinical and basic research and probably one of the largest patient populations in the world. This access to patients allows us to perform unique studies looking at the control of mucosal inflammation (Colombel, Lira, Blander, Yeretssian, Esplugues, Mehandru, Cerutti), lymphocyte/ epithelial cell interactions (Dahan, Berin, and Lira) and the microbiome (Lira, Colombel, Faith, Clemente, Furtado, Merad, Alexandropoulos, Cerutti). Our investigators study the ontogeny and composition of mucosal immune cell populations (Merad, Alexandropoulos), cellular migration (Lira, Furtado, Esplugues), signaling (Ting, Chen, Xiong, Yeretssian), apoptosis and necrosis (Blander, Ting, Yeretssian). In the area of immunoregulation, we study the function of specific suppressor or regulatory pathways (Chen), role of complement in T cell function and transplantation (Heeger) and the role of microRNAs in immune cell function (Brown). These are emphasized translationally by several human disorders. Funding for the mucosal immunology program has been provided by a program grant in innate and adaptive immunity in IBD (Lira, Blander, Xiong, Ting), several RO1s, and a generous gift from the Helmsley Foundation that has allowed us to further recruit into the Institute (Cerutti, Espluges, Yeretssian, Faith) and establish a germ-free animal facility for studies on the microbiome.

Immunodeficiency Our investigators focus on basic aspects of B cell function (Cortes, Cerutti, Cunningham-Rundles), and we have an outstanding clinic in Primary Immunodeficiency. Charlotte Cunningham-Rundles runs the largest Primary Immunodeficiency clinic in the Northeast and possibily the US. In addition to a program grant and several RO1s, there are several ongoing clinical trials. Food allergy Hugh Sampson runs the pediatric food allergy clinic, although some adults are seen as well. Clinical research, clinical trials, and basic research are all ongoing and well funded. Cecilia Berin studies the role of physiologic or environmental adjuvants that may promote the development of allergic sensitization by altering the phenotype of mucosal dendritic cells and Paula Busse studies mechanisms of allergies in older populations. XiuMin Li and Madhan Masilamani study immunopathogenic mechanisms underlying food allergy and novel therapies for these allergic diseases. The results of these efforts are a wellfunded program in food allergy (Sampson and Berin). Human Immune Monitoring Center A recent effort spearheaded by Miriam Merad and Sacha Gnjatic, focus on the development of platforms to evaluate the immune system in health and disease. State-of-the-art technologies (mass cytometry, seromics, TCR sequencing) are being implemented to assess the immune system in patients receiving different therapy modalities. Immunotherapy 3

Our efforts in immunotherapy originate from the pioneering work done by Lloyd Mayer and Charlotte-Cunningham Rundles, who first applied biologicals to the treatment of immunodeficiencies and inflammatory bowel disease at Sinai. This work expanded into the treatment of other immune-based diseases, with polyclonal and monoclonal antibodies, cytokines and fusion proteins. Subsequent work by Hugh Sampson and his team has focused on development of novel therapeutic modalities for food allergy. A major effort in this area is underway. More recently, a major effort in cancer immunotherapy has been launched by Steven Burakoff at the Tisch Cancer Center, who has recruited Nina Bhardwaj to lead the cancer immunotherapy program. The Center of Therapeutic Antibody Development led by Tom Moran produces human monoclonal antibodies using both mouse models and human cells and is an important resource available for the immunology community. A detailed description of our programs is found within this document. Science productivity Scientists form the Immunology Institute and their groups have published 622 papers in the period 2007-2014. Many of these papers appeared in high impact journals (Nature, Cell, Science, Nature Immunology, Immunity, JEM, JCI, JACI). A list of papers published since 2013 is found in the Appendix I.

Funding Members of the Immunology Institute (33 out of 42 faculty) raise approximately US$ 34 million dollars in direct funds yearly. Most of these funds originate from NIH grants and contracts (US$ 21 million). Grants form pharmaceutical sector (US$ 4 million) and foundations (US$ 9 million) also support our scientists. Physical space The Immunology Institute members are located throughout the Icahn School of Medicine campus and occupy 36,488 sq ft of wet lab space ( 868 sq ft/investigator). Resources Several Shared Research Facilities are available to our community including Imaging, Mouse Genetics, Genomic Cores and the Immunomonitoring Center. Interaction with other Institutes/Clinical divisions Interactive programs are carried out by several labs in the Institute with the members of the Transplant Institute and with the Diabetes, Obesity and Metabolism Institute. Examples include research in thyroid autoimmune disease (Davies, Tomer) and in Type I diabetes (Tomer, Brown) and transplantation (Murphy, Heeger, Ochando). Basic mechanisms of autoimmunity and transplant biology such as central mechanisms of T cell selection (Alexandropoulos) and mechanisms of tolerance (Ochando, Heeger) are being explored. We have developed a joint exploratory program in neuroinflammation with the Friedman Brain Institute and these 4

interactions have led to a recently funded NIH application (Russo, Merad). Our scientists participate in collaborative programs with scientists and clinicians at the Tisch Cancer Center, at the Icahn Institute for Genomic Sciences, and in the Department of Medicine (Divisions of Clinical Immunology, Gastroenterology, Rheumatology, and Dermatology). The focus of study in most cases is the role of inflammation in many disease processes. An excellent example of this is a joint project supported by Janssen Pharmaceuticals on the mechanisms underlying the development of inflammatory bowel disease. This involves immunologists (Lira, Xiong, Dahan), gastroenterologists (Colombel, Sands), geneticists (Cho) and computational biologists (Schadt, Kasarskis). Other efforts involving the study of rheumatoid arthritis (Gulko) and dermatological disorders (Guttman) are underway. Education With the establishment of the Institute, we created a MD/PhD and PhD program in Immunology. Our scientists and their trainees meet weekly and discuss their findings at the Work-inprogress Seminar Series. Once a month, we host internationally renowned immunologists at the Immunology Seminar Series, and once a year, we hold an Institute retreat to bring together all of the laboratories. The goal remains to promote a highly interactive productive environment for the training of graduate students, postdoctoral fellows, junior, and senior faculty. Our recruitments over the past 7 years have already reaped benefits in terms of creating a sense of community and an interactive training environment. Our Work-in-progress meetings have fostered collaborations that led to project grants. Both the

immunodeficiency PPG and mucosal immunology/IBD PPG arose from these meetings. They have also solidified Immunology as a distinct entity that is easily recognized by students and postdoctoral fellows as a desirable area for training. Recruitment of students has increased tremendously, with the pool of applicants doubling in the last years. Furthermore, we have had a training grant for over 8 years that funds postdoctoral fellows and graduate students. In addition to our graduate program, that focuses on the training of PhDs and

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MSTP students, our faculty maintains a strong commitment to the mentoring of medical students, residents, and clinical fellows. Immunology Institute website General and relevant information of the weekly activities of the Institute can be found at our website: http://www.iisinai.org/

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Mucosal Immunology

The Mucosal Immunology program at Mount Sinai began with Dr. Lloyd Mayer, who continued a long-standing tradition of excellence in studies pertaining to inflammatory bowel disease (IBD). This tradition started in 1932, when Dr. Burrill Crohn first described Crohn’s disease. The program expanded in 2007, when Dr. Sergio Lira and Dr. Mayer were named co-Directors of the Immunology Institute. After receiving a Hemsley Trust Grant in 2009, Mount Sinai expanded a pre-existing roster of internationally recognized immunologists by recruiting four new faculty members, including Drs. Andrea Cerutti, Garabet Yeretssian, Enric Esplugues and Jeremiah Faith. Goals The Mucosal Immunology program has the following general goals. 1) To make breakthroughs in our understanding of the intertwined biological networks mediating gut homeostasis, including the immune system, epithelium, mucus and microbiota. 2) To make major advances in our understanding of IBD by taking advantage of fundamental discoveries in the regulation of gut homeostasis. 3) To translate advances in basic biology into more effective therapies for IBD. The complementary expertise and highly collaborative nature of our team is ideally suited to “crack” the inflammatory codes underpinning IBD and to generate “out-of-the-box” ideas for more effective therapies.

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Team The labs of Drs. Blander, Cerutti, Merad, Lira, Furtado, Xiong, Berin, Mehandru, Esplugues, Faith, Yeretssian and Ting do basic research in mucosal immunology. We have a strong collaborative program with the Helmsley IBD Center at Sinai. In addition, the Immunology Institute is home to members of the IBD center, such as Drs. Colombel and Cho, who conduct clinical research and genetic studies in IBD populations. Themes Ontogeny, trafficking, and function of mucosal immune cells. The Merad group studies the biology of the mononuclear phagocyte system. They have identified distinct precursors of tissue macrophages under steady-state conditions and inflammation, completely revising the existing paradigms. This group also identified ontogenetically distinct subsets of mucosal dendritic cells (DCs). Ongoing studies are aimed at exploring the contribution of individual DC and macrophage subsets to IBD. The Lira group studies how chemokines regulate the homeostatic and inflammatory influx of specific leukocytes into the intestine and how chemokines regulate the development and maintenance of gut lymphoid structures. Ongoing studies are evaluating the role of individual chemokines in different disease settings, Including IBD. The Merad and Brown groups have collaborated to dissect the transcriptional networks and microRNAs that regulate the development and tolerogenic function of mucosal DCs and macrophages under steady-state conditions and after immunization. The Merad group has identified GM-CSF as a tissue-specific regulator of DCs and macrophages. Their groups jointly evaluate the transcriptional and microRNA profiles of

DCs in IBD and aim to identify novel therapeutic targets along the GM-CSF and miR-126 axis. The Blander group identified prokaryotic messenger RNA as a prototype “vita-PAMP” recognized by the TLR adaptor TRIF along with the NLRP3 inflammasome. Ongoing work is defining the innate and adaptive pathways mobilized by live bacteria to generate more effective vaccines. This group also showed that Rab11a stocks the endosomal recycling compartment (ERC) in DCs with MHC-I. TLRs control MHC-I delivery from ERC to phagosomes via MyD88-IKK2 phosphorylation of SNARE SNAP23. In this way, selective MHC-I recruitment to phagosomes containing TLR ligands favors those phagosomes for cross-presentation. The Cerutti group elucidated how BAFF and APRIL from mucosal DCs activate class switching and IgA production in mucosal B cells through the TACI receptor. These studies involved extensive collaborations with Dr. Charlotte Cunningham-Rundles from the Immunodeficiency Program and led to the identification of TACI interaction with the TLR adaptor MyD88 and to the development of a collaborative program (PPG). Additional collaborations with Drs. Lira, Merad and Blander focus on the role of TACI and its homologue BCMA in gut homeostasis and inflammation. The Cerutti group also elucidated the mechanism by which mucosal B cells switch from IgM to IgD to establish a crosstalk with IL-4-producing basophils. Ongoing collaborations with the Allergy Program including Drs. Sampson and Berin, aim at defining the role of IgD in mucosal homeostasis and inflammation, including allergy. The biology of Ig gene diversification in B cells is also tackled by Dr. Cortes. Interplay between mucosal immune cells, mucus and the microbiota. The Cerutti group, in collaboration with Dr. 8

Blander, found that the microbiota inhabits a mucus niche that establishes a functional interplay with the gut immune system. Indeed, the gut-specific mucin MUC2 interacts with luminal bacteria and constraints their immunogenicity by providing regulatory signals to antigen-sampling DCs. Current collaborations with Drs. Merad, Lira, Sampson and Berin are evaluating the perturbations and anti-inflammatory potential of MUC2 in IBD. The Lira group studies the contribution of the microbiota to the development of IBD and cancer. Recent work shows that host and site-specific microbiota controls the development of neoplasia in genetically susceptible mice. These studies were done in close collaboration with the Merad, Faith and Clemente groups. The Faith group studies how diet affects the microbiome. They found that diet predictably controls the relative abundance of gut microbes and that the majority of gut strains in healthy individuals remain stable throughout life. The Faith group also developed a systematic and unbiased platform to identify the microbial strain or group of strains that modulate key aspects of mucosal immunology, with the goal of generating next generation probiotic combinations for treating IBD. Current studies in the Faith lab investigate the stability of the gut microbiota in individuals with IBD and the extent to which microbiota stability can serve as a predictive indicator of disease onset and progression. Additional studies aim at implementing dietary interventions to modulate the pathogenesis of IBD. The Faith group actively interacts with clinicians at the IBD center. Regulation of mucosal inflammation by cytokines. The Merad group found that GM-CSF-producing ILCs inhibit gut inflammation by stimulating the production of tolerogenic factors such as retinoic acid in gut DCs. In the absence of GM-

CSF, gut DCs become less competent to promote the formation of Treg cells with anti-inflammatory activity, which predisposes to inflammation. Ongoing studies in collaboration with Drs Cho and Colombel (IBD center) evaluate the pathogenetic role of antibodies to GM-CSF and polymorphisms of the gene encoding GM-CSF during IBD. The Cerutti group identified mucosa-like ILCs that activate splenic MZ B cells through a GM-CSF-regulated pathway involving neutrophils. Studies on marginal zone (MZ) B cells involved collaborations with Drs. Blander, Merad, Xiong, and Cunningham-Rundles. Ongoing studies in collaboration with Dr. Merad are deciphering how a dysregulation of this pathway may hamper antibody responses to capsular polysaccharides during IBD. The Blander group showed that infection and apoptosis coinduce inflammatory and anti-inflammatory cytokines critical for TH17 responses. These findings set the stage for defining the antigenic specificity of TH17 cells and open new avenues for a better understanding of TH17 cell responses during IBD. Studies on trafficking and function of mucosal Th17 cells are also developed by Drs. Esplugues, Xiong and Ting. The Lira group was the first to show that IL-23 promotes inflammation through pathways previously attributed to IL-12. Their current studies evaluate how IL-23 modulates ILCs to regulate mucosal immunity and inflammation. Achievements •

A program project grant (PPG) on mucosal immunology. The present members of this grant are Drs. Lira (PI), Blander, Ting and Xiong. This grant allowed for the generation of several collaborations within the Institute, the development

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of a pathology core (under Dr. Harpaz), and a mouse genetics core (under Dr. Lira). These cores provide for access to pathological analyses and access to engineered mouse models. A grant from the Helmsley Trust, which has allowed for recruitment of new faculty (Cerutti, Faith, Esplugues, Yeretssian). This grant also established the Helmsley IBD center and the recruitment of outstanding gastroenterologists (Colombel) and geneticists (Cho), have joined the Institute and contributed to development of joint programs with the basic immunologists. This has led to joint programs such as SUCCESS (supported by philanthropy) and a program with Janssen Pharmaceuticals. The establishment of a microbiome program and the development of a germ-free facility (under Dr. Faith) that will be critical for stuies involving the microbiome. Publications in major scientific journals (Cell, Nature, Science, Nature Immunology, Immunity, J. Exp. Med., JCI, etc)

Future Gut homeostasis and IBD involve intertwined biological networks that include the immune system, epithelium, mucus and microbiota. Our core team includes investigators highly recognized in the fields of DCs, macrophages, microbial sensing, B cells, chemokines and microbiota. To optimize our program and uncover how complex mucosal biological networks deviate toward inflammation in response to both environmental and genetic factors we envision: •

Recruitment of experts in epithelial cell biology, microbiology, metabolomics and glycobiology. In particular we consider the area of glycobiology an area of growth in mucosal biology. Mucus contains hyperglycosylated mucins



that anchor and regulate the composition of the microbiota. Conversely, the microbiota stimulates mucin production to generate energy and growth signals from mucin-associated glycans. Of note, perturbations of mucin glycosylation brought about by primary or acquired alterations of specific glycosyla transferases (e.g., FUT2) play an important role in the pathogenesis of IBD. These alterations may alter the composition of the microbiota and the generation of tolerogenic DCs. We believe that defining the glycobiome of individual IBD patients may have both biological and clinical (i.e., predictive) values. Better integration with bioinformaticians at the Genomic Institute to facilitate the analysis of data emerging from

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transcriptome, microbiome, metabolome, and glycobiome studies. Support for studies centering on human mucosal immunology. We consider support of the Immunomonitoring Center and creation of a tissue repository for the collection, storage and distribution of mucosal samples as important factors for the improvement of existing interactions of basic scientists with our clinicians. Wide dissemination of novel technologies, including CRISPR/Cas, Mass Cytometry and Seromics to the study of mucosal immunology/IBD. These technologies are currently spearheaded by Drs. Sergio Lira, Brian Brown and the Immunomonitoring Center.

Andrea Cerutti graduated in Medicine and specialized in Hematology at Padua University, Italy. After completing a postdoctoral fellowship in immunology he was appointed Assistant Professor (2001) and Associate Professor (2006) of Pathology at Weill Medical College of Cornell University. He joined the Immunology Institute of Icahn School of Medicine at Mount Sinai in 2010 as Professor of Medicine. Dr. Cerutti is a member of the Henry Kunkel Society and the American Society for Clinical Investigation, and co-organized two Keystone Symposia meetings on B cells.

and homeostasis and the mechanisms by which mucosal IgD regulates immunity and inflammation, including allergy. IgA-interacting mucins and gut homeostasis

Research Interests

We take advantage of both mouse and human models to explore the function of the IgA-interacting mucin MUC2 in gut homeostasis. We found that MUC2 constraints the immunogenicity of gut antigens by providing regulatory signals to antigen-sampling dendritic cells through a receptor complex involving Dectin-1, FcgammaRIIB and galectin-3. Our studies highlight a close interplay between MUC2-secreting goblet cells and the gut immune system and suggest that mucus actively delivers anti-inflammatory signals in addition to forming a physical barrier. The role of MUC2 in inflammatory bowel disease is under evaluation.

IgA and IgD production by mucosal B cells

IgM, IgG and IgA production by splenic B cells

We use both mouse and human models to gain new insights into the biology of IgA and IgD, two antibody classes released by intestinal and respiratory B cells, respectively. We have shown that mucosal dendritic cells and epithelial cells enhance IgA production by releasing BAFF and APRIL (NI, 2002; Immunity, 2007; NI 2009), two class switch-inducing TNF family members that activate a TLR-like pathway involving the TACI receptor on B cells (NI, 2010). We have also found that HIV alters mucosal IgA production by interfering with signals from CD40L, a TNF family member expressed by T cells (NI, 2006; NI 2009). Finally, we have demonstrated that a unique subset of mucosal B cells switches from IgM to IgD to establish a crosstalk with IL-4producing basophils (NI, 2009). We currently study the role of TACI and BCMA (another BAFF/APRIL receptor) in gut immunity

We use mouse, rhesus macaque and human models to better understand the biology of marginal zone (MZ) B cells, an innatelike B cell subset involved in rapid antibody responses to bloodborne viral and bacterial carbohydrate antigens. We recently found that MZ B cells receive BAFF and APRIL helper signals from neutrophils (NI 2011). We also identified a new subset of splenic innate lymphoid cells (ILCs) that have mucosa-like properties and release the neutrophil-activating cytokine GMCSF (NI 2014). We are currently deciphering the stromal and immunological signals that regulate the activation of splenic ILCs, the relationship of splenic ILCs with the gut, and the relevance of splenic ILCs and GM-CSF to protective antibody responses against HIV and encapsulated bacteria.

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Sergio Lira received his MD from the Universidade Federal de Pernambuco in Brazil and his PhD in Physiology and Pharmacology from the University of California at San Diego. He did his postdoctoral training at the Roche Institute for Molecular Biology in Nutley, NJ. After his postdoctoral training he worked for 11 years in the pharmaceutical industry, first at BristolMyers Squibb and then at Schering-Plough. He is currently the The Leona M. and Harry B. Hemsley Charitable Trust Professor of Immunology at the Icahn School of Medicine at Mount Sinai in New York, where he is the Director of the Immunology Institute. He has organized international meetings in this field, including the 2003 Keystone Symposium on Chemokines, the 2006 Gordon Research Conference on Chemotactic Cytokines, and the 2012 Keystone Symposium on Chemokines and Leukocyte trafficking. He was elected to the Henry Kunkel Society in 2006 and to the Association of American Physicians in 2008. He is a member of the Board of Scientific Advisors of the National Cancer Institute and Visiting Professor at the Southern Medical School in Guangzhou, China.

to the intestine. We have shown that chemokines regulate the homeostatic and inflammatory influx of leukocytes into the intestine and that they are important for the development and maintenance of lymphoid structures in the intestine (MI, 2009, 2010, 2014; JCI, 2011, Immunity 2013)

Research Interests

Role of genetic variants in the development of IBD

Regulation of leukocyte trafficking into the intestine during homeostatic and pathologic conditions

We are using CRISPR technology to generate mouse mutants carrying SNPS associated with IBD. We expect to learn how these genetic variants increase risk or protect humans from IBD.

Our lab uses genetic approaches to study the role of chemokines and their receptors in the migration of specific leukocyte subsets

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Role of IL-23 in mucosal inflammation Studies done by our lab were the first to show that IL-23 expression promotes inflammation (JI, 2000). In collaboration with Cua and Kastelein we also showed that many of the inflammatory phenotypes previously attributed to IL12 were in fact driven by IL-23 (Nature, 2002). We currently study the role of IL-23 in mucosal immunity, focusing on its ability to promote development of innate lymphoid cells. Role of the microbiota in mucosal inflammation and cancer Our lab studies the contribution of the microbiota to the development of inflammatory bowel diseases and cancer. Our recent work suggests that host and site-specific microbiota is important for development of neoplasia in genetically susceptible mice (JEM, 2014).

Jeremiah Faith received his PhD in Bioinformatics and Systems Biology from Boston University. He did his postdoctoral training in the laboratory of Jeffrey Gordon at Washington University in St. Louis Medical School with a focus on the structure and function of the gut microbiome in healthy individuals. He is currently an Assistant Professor in the Immunology Institute and the Institute for Genomics and Multiscale Biology in the Icahn School of Medicine at Mount Sinai in New York. His research focuses on modeling the interactions between diet, gut microbes, and host physiology with an emphasis on Inflammatory Bowel Disease. Research Interests Quantifying the influence of diet and the gut microbiota on host health and disease Using gnotobiotic mice harboring a defined collection of human gut microbes and systematic dietary perturbations, we found the abundances of gut microbes can be predictably controlled with diet. We are currently using these results to implement dietary interventions that modulate pathogenesis in mouse models of colitis. Using a combination of dietary manipulations and gnotobiotic animals, we are quantifying the individual contributions of diet and the microbiota on disease

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pathogenesis as well as synergistic interactions between these two key environmental parameters that influence health. Identifying microbial strains that modulate host phenotypic variation Microbiome studies to understand the role of our gut microbes in health and disease have largely been descriptive in nature or have focused on identifying a stain capable of modulating a property of host physiology. By combining high throughput culturing methods with a gnotobiotic-screening pipeline, we developed a systematic, unbiased platform to identify the strain or group of strains in a microbiota that confers a phenotype of interest on the host. We are apply this technology to identify microbes that modulate aspects of mucosal immunology and inflammatory diseases with the goal of generating next generation probiotic combinations for treating human disease. The stability of the human gut microbiota The gastrointestinal tract harbors roughly 100 different species of bacteria that are unique to each individual. Despite numerous daily encounters with a microbe-rich world, we found that the majority of strains in healthy individuals remain stably colonized throughout life. We are currently investigating the stability of the gut microbiota in individuals with disease and the extent to which microbiota stability can serve as a predictive indicator of disease onset and progression.

Miriam Merad was trained as an Oncologist in Paris, France and obtained her PhD in Immunology from University Paris VII and Stanford University in 2001. She was recruited to the Icahn School of Medicine at Mount Sinai School in 2004 and was promoted to the rank of Associate Professor with Tenure in 2007, and to Full Professor in 2010. Dr. Merad serves as the Co-Leader of the Cancer Immunology Program at the Tisch Cancer Institute and the Associate Director for the M.D.; Ph.D. program at Mount Sinai Medical School. Dr. Merad’s laboratory studies the mechanisms that regulate the development and function of innate myeloid cells including dendritic cells, Langerhans cells and macrophages. In 2013, Dr. Merad was the primary organizer of the Keystone conference on dendritic cell biology and was elected to the “American Society of Clinical Investigation”. She has authored more than 100 primary papers and review articles in high profile journals and obtained extensive NIH funding for her studies on dendritic cells and macrophage biology in mice and humans. Dr. Merad leads the Human Immunomonitoring Center, which provides cutting edge technology for comprehensive analysis of the human immune system. Research interests Regulation of macrophage development and function

and

dendritic

cell

(DC)

In contrast to the dogma that most macrophages derive from circulating monocytes, we have showed that most tissue

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resident macrophages arise from embryonic precursors that take residence in tissues prior to birth, where inflammatory macrophages mostly derive from circulating monocytes (Merad et al. Nature Immunology 2002; Ginhoux et al. Nature Immunology 2006; Ginhoux et al. Science 2010; Hoeffel et al. JEM 2012; Hashimoto et al.; Immunity 2013). We are currently deciphering the contribution of these distinct macrophage lineages to disease pathogenesis. In contrast to macropahges, tissue DC arise from adult bone marrow precursors along two distinct developmental pathways (Ginhoux et al, JEM 2009; Bogunovic et al. Immunity 2009; Helft et al. JCI 2012). We are currently examining the contribution of distinct DC subsets to tissue integrity and to antimicrobial and antitumor immunity. Maintenance of Mucosal Tissue Integrity One of the focus of our laboratory in the recent years has been the identification of tissue-derived factors that contribute to survival and function of macrophage and DC in barrier tissues. Work in this area includes the characterization of IL-34 as a critical factor controlling development of Langerhans cells and microglia (Greter et al, Immunity 2012). We have also shown that that GM-CSF is produced by gut tissue resident innate lymphocytes in response to commensal microbial signals to instruct macrophage and DC regulatory function and promote Treg homeostasis in the steady state (Mortha et al. Science 2014). More recently we uncovered a neuronal-macrophage crosstalk required to maintain intestinal motility (Muller et al. Cell, in press). In addition to gut tissue macrophages, we study the regulation of the development and function of tissue resident phagocytes in other barrier tissues including the skin and lung.

Brian Brown received his PhD in Pathology and Molecular Medicine from Queen’s University in Canada. He conducted his postdoctoral training at the San Raffaele Scientific Institute in Milan, Italy under the supervision of Dr. Luigi Naldini and Maria Grazia Roncarolo. He became faculty at Mount Sinai in 2008, and is currently an Associate Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York, as well as a faculty member in Mount Sinai’s Immunology Institute.

Molecular regulation of dendritic cells

Research Interests

microRNA biology

Immune tolerance

Dr. Brown’s lab is studying some of the fundamental principles of microRNA biology. His lab has been at the forefront of defining the stoichiometric relationship between microRNA and target concentration. They were one of the first to show that overexpression of a microRNA’s target can lead to ‘sponging’ of the microRNA. This work has had far-reaching implications for understanding the basic mechanisms of microRNA biology and for interpreting virtually all microRNA profiling data. It also helped lead to the development by his lab, and others, of microRNA sponge and decoy vector technology. His lab is continuing to investigate the relationship between microRNA concentration and target regulation, and to identify the posttranscriptional mechanisms that control microRNA activity.

One of the main goals of Dr. Brown’s lab is to develop strategies aimed at modulating the host immune response for inducing antigen-specific tolerance or immunity. Dr. Brown developed the first microRNA-regulated vector system. This is a new approach for targeting the expression of transgenes, vectors and viruses that has now been used by numerous labs for a range of emerging therapies ranging from gene therapy to oncolytic viruses. The first system he developed utilized target sites for the pan-hematopoietic microRNA, miR-142, to de-target antigen expression from macrophages and DCs. This enabled him to prevent an immune response to the antigen and even induce antigen-specific regulatory T cells. Dr. Brown’s lab is evaluating microRNA-based targeting as a means of inducing tolerance to islet antigens and prevent or reverse the development of type I diabetes.

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Dr. Brown is also working to understand the molecular regulation of dendritic cells. In collaboration with Dr. Miriam Merad in the Immunology Institute, Dr. Brown is carrying out work to decipher the transcriptional programs that control dendritic cell development and function. Recently, his lab identified a new pathway controlling the type I interferon response to pathogen-associated nucleic acids and HIV, which involves the microRNA miR-126, and the main VEGF receptor, VEGFR2. They are now investigating how the miR-126-VEGFR2 axis’s control of the innate immune system impacts melanoma growth.

Julie Magarian Blander received her Ph.D. from the University of Pittsburgh studying tumor immunology and immunotherapy under the mentorship of Olivera Finn. She conducted her postdoctoral training with Charles Janeway and Ruslan Medzhitov at Yale University pioneering the study of the impact of Toll-like receptors on macrophage and dendritic cell function. Dr. Blander is currently an Associate Professor with tenure at the Icahn School of Medicine at Mount Sinai. She is a 2014 Leukemia and Lymphoma Society Scholar, 2011 Burroughs Wellcome Fund Investigator, recipient of the 2009 G. Jeannette Thorbecke award, 2010 Lamport award, 2011 MSSM Faculty Council Junior Faculty Award for Academic Excellence, 2008 American Cancer Society scholar, and a 2007 Searle scholar. Her research interests center on the mechanisms of innate immunity and their impact on adaptive immunity.

Demonstrated that the innate immune system specifically detects and uniquely responds to microbial viability. We coined the term ‘vita-PAMPs’ uniquely associated with viable microorganisms, and identified prokaryotic messenger RNA as a prototype vita-PAMP via the Toll-like receptor (TLR) adaptor TRIF and the NLRP3 inflammasome. Addition of prokaryotic RNA to a dead vaccine augments its performance to that of a live vaccine. Our work here continues to define the innate and adaptive pathways mobilized by live bacteria, and their exploitation for new vaccines.

Research Interests

Discovered a major reserve of MHC class I (MHC-I) molecules in endosomal recycling compartment (ERC) of dendritic cells, mobilized with TLR signals and critical for crosspresentation. We showed that the small GTPase, Rab11a, stocks the ERC in dendritic cells with MHC-I. TLRs control MHC-I delivery from ERC to phagosomes via MyD88-IKK2 phosphorylation of SNARE SNAP23, leading to stable transSNAREs connecting ERC to phagosomes. Together with TLRindependent recruitment of the MHC-I peptide-loading complex from ER-Golgi intermediate compartments, selective MHC-I recruitment to phagosomes containing TLR ligands favors those phagosomes for cross-presentation.

Defined a physiological trigger for differentiation of TH17 cells. We showed that infection and apoptosis form a unique inflammatory signal that induces a combination of inflammatory and anti-inflammatory cytokines critical for a TH17 response. These findings demonstrated coexistence of immunosuppressive apoptosis with infection, and set the stage for defining the antigen specificities of TH17 cells. Because of strong associations between TH17 cells and autoimmune disease, the potential for developing autoreactive TH17 cells in this setting is a particular focus.

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Established the first dual targeting of Toll-like and Nod-like receptors for tumor immunotherapy. We designed a tumor cell vaccination approach whereby bacterial flagellin is expressed within tumor cells to synergistically target TLRs and NLRs and mount an effective anti-tumor adaptive response. These findings urge a reconsideration of the manner in which TLR ligands are used in tumor immunotherapy, and the necessity for the inclusion of NLR ligands for improved clinical outcomes.

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Allergy

The

Jaffe Food Allergy Institute was created with an

endowment from the Jaffe Family Trust in July 1997 with the goal of establishing an internationally recognized center for the study of food allergic disorders in children known for excellence in research, patient care and education. Dr. Hugh Sampson moved from Johns Hopkins with two junior faculty recruits, Dr. Scott Sicherer and Dr. Xiu-Min Li, a research nurse coordinator, Ms. Sally Noone, and a post-doctoral fellow, Dr. Kirsten Beyer. From this original group of 5 individuals, the Institute has expanded to over 60 members including 9 MD faculty, 3 PhD faculty, 6 research nurse coordinators, laboratory technicians, administrators and post-doctoral fellows. The Institute also hosts 1 – 2 visiting scientists from abroad each year. In the Jaffe Institute clinics, the medical faculty sees greater than 6,000 patient visits per year, providing a rich resource for over a dozen translational research studies conducted by Institute members. Central to the diagnosis and management of food allergies is a better understanding of oral tolerance and the underlying immunopathogenic mechanisms involved in allergic reactions. In recent years a variety of clinical trials have been launched for the treatment of milk, egg, peanut and wheat allergies using a variety of immunotherapeutic approaches including oral, sublingual and epicutaneous immunotherapy, and the use of a novel engineered recombinant peanut protein delivered rectally in E coli. While the latter approach proved extremely effective in a murine model of peanut allergy, Phase I clinical trials in man revealed more significant adverse allergic symptoms than anticipated. As outlined below, these clinical studies have been accompanied by basic immunologic studies attempting to better understand the immunopathogenesis of

18

food allergic disorders and changes in basic immune responses secondary to various immunotherapeutic approaches. Goal To help those with food allergies live safer and healthier lives through comprehensive care, education, and innovative research to find a cure.” Team Sampson Lab Dr. Sampson’s laboratory, which has been continuously funded by the NIH and various foundations, has focused on a number of areas related to food allergy. Early studies involved the development of murine models of food-induced anaphylaxis, which developed markedly elevated levels of food-specific IgE and experienced anaphylactic symptoms when fed the food allergens. In addition to studying basic immunologic mechanisms of food allergic reactions, these models were used to develop a number of therapeutic approaches to treat food allergy, including an engineered recombinant peanut protein vaccine, an herbal formulation for treating food allergy, and more recently a nanoparticle-based and DNA-plasmid chimerabased peanut vaccines. The Lab has also focused on the identification of major allergenic proteins within foods and has generated a repository of food protein cDNA’s that can be used for generating recombinant proteins for diagnostic tests and therapeutic vaccines. A focus on the interaction between IgE molecules, food proteins and clinical reactivity led to the finding that about 80% of young children with milk or egg allergy generate IgE antibodies

primarily to conformational epitopes and therefore can tolerate heat-denatured milk/egg proteins, and that introduction of these heat-denatured proteins into the diets of milk/egg allergic children accelerates the development of full tolerance. A number of basic mechanistic studies have been conducted to better understand the role of Treg cells and Th2 and effector cell (mast cells and basophils) suppression in the acquisition of clinical desensitization and tolerance. Using a novel peptide-based microarray developed by the Lab team, work over the last several years has shown the correlation between clinical reactivity, persistent clinical allergy and severity with patient IgE antibody binding to specific sequential epitopes on major food allergenic proteins. These studies have led to the development of a high through-put Luminex-based assay that is being developed in collaboration with Genisphere®. Recent studies also suggest that early monitoring of IgE and IgG4 epitope specific antibody responses will enabled physicians to better implement and administer oral immunotherapy. Li Lab Dr. Li and her team have focused on developing novel therapies including traditional Chinese medicines for food allergy and asthma, and the basic immunologic effects of these preparations. One project involves the development of a Chinese herbal medicine formula, FAHF-2 (food allergy herbal formula 2) for treating food allergies. Through NIH grants and foundation support, they have successfully completed the transition from pre-clinical studies to a Phase I and most recently a Phase II trial. The Phase I trials demonstrated the high safety profile of FAHF-2 and suppression of basophil activation and diminution of Th2 polarization of FAHF-2, reproducing

19

findings seen in the murine model. The initial Phase II trial was hampered by non-compliance due to the high daily pill intake required, but a new refining process has led to an 80% reduction in the daily dose requirement, and a new Phase II trial has just received funding. A number of active compounds comprising FAHF-2 have been isolated and identified, and their effects on immune functions elucidated. In addition, Dr. Li’s team has developed a novel herbal formulation, ASHMI, for the treatment of asthma. In Phase II clinical trials, ASHMI was shown to be an effective stand-alone asthma therapy for moderate to severe asthma when compared to prednisone, but with much less adverse side-effects. The combination of ASHMI and inhaled steroids was shown to be safer and more effective than steroid alone in children. Preclinical studies have demonstrated that ASHMI induces more long-lasting protection than corticosteroids in both eosinophil and neutrophil predominant models. Ongoing studies include the development of a new version of ASHMI by combining refined sub-fractions with more potent effects on bronchial smooth muscles, goblet cell secretions and immune function to increase pharmacological potency and ease of clinical use. Berin Lab The Berin Laboratory is focused on understanding the immune basis of allergy and tolerance to foods. Using murine models of food allergy, they have studied how interactions between intestinal epithelial cells, dendritic cells, and T cells contribute to sensitization to foods and to gastrointestinal manifestations of food allergy. Epithelial cells form the interface between the external environment and the mucosal immune system, and the Berin lab has made significant contributions to our

understanding of the contribution of epithelial cells to the pathogenesis of food allergy. They identified epithelial expression of CD23, the low-affinity IgE receptor, as a major mechanism for uptake of allergens from the gut lumen. They have also delineated the role of epithelial-derived cytokines and chemokines in the inflammatory response to food allergens in the intestine. Their work has also led to an understanding of how gastrointestinal dendritic cells orchestrate the development of allergic sensitization to foods. Current areas of focus include the use of these models to develop and refine novel immunotherapies for the treatment of food allergy, as well as to understand the basis of food allergenicity. In addition to mouse models of food allergy, the Berin Laboratory works closely with clinical collaborators in the Jaffe Food Allergy Institute in order to understand the immune basis of allergy and tolerance to foods. As part of the mechanistic core for the NIH-sponsored Consortium for Food Allergy Research, they have developed novel approaches to immunophenotyping the response to foods, including sensitive ex vivo detection of low-frequency allergen-specific T cells, CyTOF-based phenotyping, and transcriptional profiling of responses to allergen. By applying these approaches to subjects undergoing experimental allergen immunotherapy, the goal is to identify novel mechanisms and therapeutic targets to reestablish immune tolerance to foods.

• • •

Diagnosis •

• •

Epidemiology

20

Demonstrated the relationship between individual foodspecific serum IgE levels to clinically reactive food allergy and established diagnostic predictive values that are now used worldwide Identified important component proteins of food allergens for improving diagnostic accuracy Developed a peptide microarray that allows identification of allergenic epitopes in foods, which provide more specific information about clinical reactivity, severity and long-term outcome

Treatment •

Achievements Over the years, members of the Institute have achieved a number of major milestones:

Identification of risk factors for food-induced anaphylaxis, a severe and potentially fatal allergic reaction Demonstrated over a tripling of peanut allergy prevalence in the U.S. pediatric population since the late 1990’s Discovered that food allergy is the major cause of eosinophilic esophagitis (an inflammation of the esophagus) in most children

• •

Demonstrated that heat-denatured (baked) forms of milk or egg are tolerated by a majority with those allergies and that introduction of baked- milk/egg products into the diet of those milk/egg allergic children accelerates the development of full tolerance to all forms of these foods Conducted studies of novel therapies using ingredients from traditional Chinese medicine Developed a novel food allergy vaccine using engineered mutated peanut proteins

• • •

Conducted the first placebo-controlled study of egg oral immunotherapy Conducted the first placebo-controlled trial of dual therapy (immunotherapy and anti-IgE) Conducted the first placebo-controlled trial of anti-IgE (TNX-901 & omalizumab) for food allergy

Future Recently recruited faculty will expand the scope of investigation of food allergy in the Institute. Dr. Supinda Bunyavanich, MD, and others are studying how food allergic patients’ genetic predisposition is dynamically shaped by eating food during a food allergic response. Using blood from peanut allergic  

21

patients undergoing oral peanut challenges, she is analyzing how the interpretation and transcription of their DNA is modified by food allergen exposure. In conjunction with Drs. Jose Clemente, PhD, and Jeramiah Faith, PhD, members of the Institute will evaluate the role of the gut microbiota in shaping the allergic and tolerogenic response to foods. Finally the Sampson and Berin labs will continue to investigate the immunologic effects of novel immunotherapies, including a nanoparticle-based peanut vaccine, algae-based engineered peanut protein vaccine and a T-cell peptide-based peanut vaccine in clinical trials, and attempt to identify biomarkers of tolerance induction.

Hugh A Sampson is the Kurt Hirschhorn Professor of Pediatrics, the Dean for Translational Biomedical Research, PI and Director of Conduits; Institutes for Translational Sciences, and the Director of the Jaffe Food Allergy Institute at the Icahn School of Medicine at Mount Sinai. Dr. Sampson completed his allergy/immunology fellowship training at Duke University in 1980 and was a faculty member in the Division of Allergy/Immunology at Duke University and then Johns Hopkins University before coming to Mount Sinai. He has published over 400 articles and 60 book chapters on food allergic disorders and co-edited four books, and was elected to membership in the Institute of Medicine of the National Academies in 2003 for his research in food allergies. Research Interests Mechanisms of Allergic Reactions to Foods. Dr. Sampson’s research focuses on food allergic disorders including the immunopathogenic role of food allergy in atopic dermatitis, eosinophilic esophagitis and anaphylaxis. His lab studies the role of food allergen epitope-specific IgE, histamine-releasing factors, and T cell responses in the clinical manifestations of these disorders and changes that are associated with the development of natural tolerance. Characterization of Food Allergens. In an attempt to better understand the difference between individuals with “sensitization,” i.e. presence of food-specific IgE antibodies, and

22

those with “symptomatic allergic reactions,” and to explain the small minority of foods in the diet that account for over 90% of food allergic reactions (milk, egg, peanut, tree nuts and seafood), the lab has focused on identifying and characterizing component proteins within foods that account for allergic reactivity. The lab has also focused on the epitope specificity of IgE binding to these allergenic proteins and is currently developing a high throughput assay that is more specific than conventional diagnostic tests and provides information regarding natural history and severity of potential allergic reactions. In addition, this work led to finding that ~80% of young children with milk and egg allergy can tolerate these foods in a heat-denatured (baked) form, which when introduced into the diet, accelerate the induction of natural tolerance, a practice that has now become the standard of care for children with milk and egg allergies. Immunotherapy for Induction of Desensitization/Tolerance to Food Allergens. Dr. Sampson is the PI of the NIH-sponsored Consortium on Food Allergy Research and an AADCRC program project conducting a number of clinical trials investigating novel therapies for the treatment of food allergy. These trials include the use of oral immunotherapy, sublingual immunotherapy, epicutaneous immunotherapy, and the use of a novel engineered recombinant peanut protein vaccine. Dr. Sampson and his team are currently developing a peptide-based vaccine and a CpG-nanoparticle-based vaccine for treating peanut allergy, the latter of which is under review for a phase I clinical trial.

M. Cecilia Berin received her PhD in Medical Sciences (Physiology & Pharmacology) from McMaster University in Hamilton, Canada. She completed postdoctoral training in mucosal immunology at the University of California, San Diego prior to joining the Icahn School of Medicine at Mount Sinai as faculty. She is currently an Associate Professor in the Department of Pediatrics, Division of Allergy and Immunology. Research Interests Mechanisms of allergic sensitization to foods The default immune response to antigen exposure through the gastrointestinal tract is active regulatory tolerance. Dr. Berin’s laboratory is interested in understanding how these mechanisms are subverted to result in the generation of Th2biased immunity and generation of allergen-specific IgE. Her work has focused on the communication between gastrointestinal epithelial cells, dendritic cells, and T cells in the generation of allergic sensitization. Current work is focusing on innate responses to food allergens and the regulation of sensitization through epicutaneous exposure. Pathophysiology of IgE-mediated and non-IgE-mediated reactions to foods In allergic individuals, oral exposure to food allergens can result in a diverse set of manifestations affecting the gastrointestinal tract, skin, and lung. Dr. Berin’s lab has studied the mucosal

23

response to food allergens underlying gastrointestinal manifestations of food allergy, primarily focusing on the central role of epithelial cells. Her lab has shown that IgE and the low affinity IgE receptor are involved in both the facilitated antigen uptake of allergen across the epithelium and the induction of chemokines from intestinal epithelial cells. Epithelial derived chemokines (CCL20) and cytokines (TSLP) direct the recruitment and amplification of pathogenic Th2 responses in the gut. Current projects include elucidating mechanisms of gastrointestinal manifestations of non-IgE-mediated food allergy, and defining the role of neuro-immune communication in gastrointestinal and systemic manifestations of food allergy. Immunotherapy for the induction of tolerance to foods The overall mission of the Berin lab is to identify immune mechanisms for the prevention and treatment of food allergy. One approach to understanding immune mechanisms of acquired tolerance to foods is by studying patients who have outgrown their food allergies, either through intervention (allergen immunotherapy) or by natural outgrowth. In association with natural history and intervention trials being conducted at the Jaffe Food Allergy Institute, the Berin lab in collaboration with the Human Immune Monitoring Center and the Flow Cytometry Core is using novel approaches to identify mechanisms and biomarkers of acquired tolerance to foods.

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Immunodeficiency

The

Primary Immunodeficiency Program at Mount Sinai,

established in 1986 by Dr Cunningham-Rundles is now a 950 out patient service, uniquely spanning medicine and pediatric departments. Due to the numbers of patients with rare immune defects, Mount Sinai has been a site for clinical investigation, trials of cytokines, monoclonal antibodies, biologics, commercial and investigational IV and SC immune globulins, and IgA-rich preparations for reinforcing mucosal immunity. This program is a unique resource for research, and has an established DNA, RNA, cell and serum bank. The Immunodeficiency Program provides a strong clinical interface for medical student teaching, T32 Training Program, and postdoctoral training and the MD/PhD program. It also provides a major attraction for applicants to the Allergy Immunology Fellowship, one of the largest and most competitive in the United States. Since 2003, the laboratory of Benjamin Chen has been investigating the viral exploitation of T cell biology and the acquired immunodeficiency mediated by human immunodeficiency virus infection. The laboratory has been recently relocated to newly designed space in the Annenberg 23 where a state-of-the-art system for immune cell imaging has been developed. Goals The overall goals are: 1) Elucidation of the mechanisms of genetic disease and 2) Dissection of the mechanisms of acquired immunodeficiency engendered by HIV infection. Team   25

The team of investigators in the Primary Immunodeficiency Program include a medical team and research investigators in the Immunology Institute including Drs. Cunningham-Rundles, Andrea Cerutti, Patricia Cortes, George Diaz, Sergio Lira, and Adrian Ting. Added to this team are colleagues at Rockefeller University: Drs Jean-Laurent Casanova, Bertrand Boisson, and Mary Ellen Conley, and at Yale, Dr Eric Meffre. Investigators dedicated to understanding the dysregulation of the immune system during HIV infection and the acquired immunodeficiency syndrome include Drs. Benjamin Chen, Nina Bhardwaj, and Judy Aberg. Themes Genetic Defects of B cells: One of the most puzzling immunodeficiency disease, is the heterogeneous B cell defect, common variable immune deficiency (CVID). With the very large cohort of subjects with CVID who seek care at MSSM, the laboratory has investigated many aspects of this immune defect, including cellular, molecular and epidemiologic studies. Current work focuses on the genetics of these defects. One example are TACI mutations which are found in homozygous and heterozygous states in patients and their family members and lead to defects of signaling, hyperproliferation, and in the escape of autoimmune clones. Using subjects with these defects, Dr Cunningham-Rundles in collaboration with Dr. Cerutti, showed that this unique receptor uses MYD88 as a requirement for signaling. In Smith Magenis syndrome, one TACI allele is deleted, leading to a model of haploinsufficiency used in other studies. Unlike mice, human TACI is produced in two isoforms; Dr Cunningham-Rundles in recent work with Dr Adrian Ting showed that the truncated isoform is the potent signaling receptor for plasma cell generation and predict that

these isoforms control this step of B cell maturation and provide a potential target for biological intervention. Aside from TACI, other gene mutations leading to congenital B cell defects are being sought in families with several affected members, and subjects with very early onset of immune dysfunction using whole genome sequencing, with interesting candidates being several novel X chromosome genes, also BCMA, and PI3 kinase delta 110, which are being intensively studied by the investigator team. TLR Induced Antibody responses: Patients with mutations in IRAK4 and or MYD88 have severe bacterial infections but IgG responses to carbohydrate antigens appear preserved. However, the loss of CD27 IgM+ memory B cells in these subjects, suggests loss of IgM glycan “natural” antibody. Recent work of Dr Cunningham-Rundles with Drs. Cerutti and Casanova, shows a generalized loss of serum glycan antibodies (Glycomics array: http://www.functionalglycomics.org), suggesting a basis for these infections. Normal human CD27 IgM+ B cells preferentially proliferate with TLR agonists, thus loss of TLR signals impair expansion and differentiation, and potentially protective, antibodies. In other work, using high throughput sequencing, the B cell CDR3 of TLR activated B cell subjects are being examined with investigator at Stanford, showing preferential V-region usage, with secretion of poly-reactive antibodies, distinctly different from other B cell activators. Loss of B cell tolerance: In humans the mechanisms that account for auto-reactive B cells and autoantibody production remain elusive. A central B cell tolerance checkpoint in the bone marrow removes the majority of developing B cells that express poly-reactive antibodies allowing a small fraction of clones with low levels of poly-reactivity to migrate to the periphery. In this   26

continuing project Dr Cunningham-Rundles, Drs. Meffre and Cerutti, are examining B cell tolerance checkpoints using discrete genetic defects on XLP, AID, TLR, and TACI. Inflammatory/Autoimmune Disease: In a cohort of 476 subjects with CVID, a hallmark was that about 50% of patients have, in addition to infections, a group of inflammatory/autoimmune complications, which in aggregate, lead to an 11-fold increase in mortality which is not altered by standard immune globulin replacement. This issue is now the main clinical concern but it presents an unsolved puzzle as to the pathogenesis. We demonstrated an interferon signature in these subjects using RNA microarray, and we are now investigating the origin of this signature using CyTOF. Preliminary studies by Drs Cunningham-Rundles, Lira and Blander, indicate an expansion of innate lymphoid cells in blood and affected tissues. T cell interactions and viral dissemination: In the past nine years it has become increasingly clear that the human immunodeficiency virus exploits the capacity of T cells to communicate with other immune cells to facilitate viral dissemination. Research in the Chen laboratory has used advanced light and electron microscopy imaging approaches study the dynamics of virological synapse formation. These are virus-induced adhesions that communicate viral infection between immune cells. These structures share many features with immunological synapses, the fundamental unit of immune recognition, but are triggered by unique viral mechanisms and appear to facilitate immune evasion. The laboratory has specialized in developing genetic tools to elucidate the cell biology of virological synapse-mediated transmission.

Small animal models of the human Immune system: The study of human immune defects and infectious agents that only infect the human immune system has been greatly advanced by the development of highly immunodeficient mice that can be exploited as hosts for xenografted human immune stem cells. We have been developing virological tools and imaging methods that now allow us to study the behavior of HIV infected human T cells within 3-dimensional lymphoid tissue settings that do not require artificial exogenous cytokine or receptor stimulation to activate viral infection. We are developing methods to image infected immune cells within the spleen, gastrointestinal tract, and lymph nodes in humanized mice using a dedicated biohazard-contained two-photon microscopy suite in our laboratory. Achievements From the original cohort of patients brought to Mount Sinai from Sloan Kettering by Dr. Cunningham-Rundles the current service has grown steadily each year, now numbering 800 - 900 patients from the NYC, surrounding and other states. The program spans medicine and pediatrics at Mount Sinai. As of 2010 it is the largest referral site for infants with abnormally low TRECs, indicating severe T cell dysfunction such as SCID. The patient group has been a major resource for the development of grant funding, which includes a Program Project on B cell defect, now in its 11th year, as well as an R18 Demonstration and Education grant now in it 12th year, based on a computer algorithm we invented to identity undiagnosed patients with immune deficiency in electronic medical records, using disease coding. Overtime clinical trials for most of the currently licensed immune globulin products have been tests in this program, and cytokines such as gamma-interferon and IL-2, have been used in   27

various studies. In the past five years alone, research and clinical studies of the patient group has been the basis for 51 peer reviewed articles. While one of the main focuses of this program has been the B cell defects, patients with may other immune defects receive care, chronic granulomatous disease, X linked agammaglobulinemia, hyper IgE, Wiskott Aldrich syndrome, Hyper IgM Syndrome, severe combined immune deficiency, DiGeorge syndrome, as well as very rare disorders such as DOCK8, GATA2, LAD2, cartilage hair hypoplasia, XLP and NEMO defects. Another important achievements were the routine development of highly immunodeficient mice that can be exploited as hosts for xenografted human immune stem cells and the establishment of a dedicated biohazard-contained two-photon microscopy suite. Future Research in the Primary Immunodeficiency Program: With the expanding number of genetic diseases defects, we are in the midst of seeking defects that lead to impaired B cell function, using whole-genome sequencing and with the application of novel tools, new candidates are now emerging. These will lead to new insights into normal B cell function as well as opportunities for therapeutic advances. Currently a group of mutations in PI3 kinase 110 delta, now found in 50+ subjects, is attracting interest, as these are additional inflammatory complications potentially susceptible to treatment with a novel PI3 kinase110 delta inhibitor. Research in the Viral Immunodeficiency Program: We are developing new methods to correlate live light imaging

approaches with ultrastructure to better characterize the cellular structures that underlie viral transmission. We are also working to develop reverse genetic methods in our humanized mouse models to probe specific genetic pathways that support the spread of HIV through T cells. These methods will be generally applicable to create humanized models of immunity/immunodeficiency or to test gene repair approaches in stem cells from genetically deficient individuals. Clinical program: We expect further expansion of the program at Mount Sinai and the opening of a new center at one of our new sites. As subjects with primary immunodeficiency have an alarming incidence of inflammatory and autoimmune disease, more targeted immune therapies will be needed for this patients, and will be tested at this site.

  28

Charlotte Cunningham-Rundles received her bachelor’s degree from Duke University, MD from Columbia College of Physicians and Surgeons and PhD from New York University. Her internal medicine training was in at New York University Bellevue Hospital, after which she went to Memorial Sloan Kettering Cancer Center as an Associate Member and Director of the Biochemical Immunology and Immunodeficiency Laboratory. At Mount Sinai, she is a Professor of Medicine and Pediatrics and the David S. Gottesman Professor of Immunology, Program Director of the Allergy Immunology Fellowship, and acting Chief of Clinical Immunology. Dr. Cunningham-Rundles has served as Chair of NIH Allergy Immunology and Transplantation Committee, the Immunology Review Committee of NASA and served on the FDA Blood Safety and Advisory Committee, and the Medical Advisory Boards of the Immune Deficiency Foundation and the Jeffrey Modell Foundation. She is a member of the Henry Kunkel and the Harvey Societies. She is a past President of the Clinical Immunology Society and member of the Board of the American Academy of Asthma Allergy and Immunology. She is a member of the Expert Committee on Immune Deficiency, IUIS, and founder and Principal Investigator of the USIDNET, a research consortium funded by the NIH. Research Interests We investigate primary defects of human B cells, the causes, treatments and outcomes. While few of the immune defects leading to loss of B cell development known, the genetic reasons for loss of this key adaptive function remain to be elucidated. 8% of subjects with common variable immune   29

deficiency (CVID) have mutations in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a still enigmatic receptor which activates and yet regulates B cell function. We have used naturally occurring mutations in TACI to investigate signaling pathways, regulation of isotype switch, and control of tolerance in human B cells. Current studies show that differential use of TACI isoforms provides essential but unanticipated regulatory controls on plasma cell development. On whole exome sequencing, LRBA and PI3Kd gain-of-function mutations have emerged as causes of complex B cell defects with immune dysregulation and risk of lymphoma, which allow novel opportunities to understand inflammatory networks in CVID and to use targeted treatment strategies. T and B cell receptors High-through-put sequence analysis of the CVID IgH repertoire has revealed novel disease mechanisms and phenotypic features, including aberrant gene rearrangement in the bone marrow, decreased V gene replacement, decreased naïve B cell repertoire diversity, impaired somatic hypermutation, and abnormal expansion of unmutated B cell clones. Suggesting unifying stem cell defects, TCR β CDR3 TCR analyses also show increased germline sequences, and greater clonality, unrelated to age, sex, or clinical complications. Cohort studies The very large referral base for pediatric and adult patients has led to an unparalleled patient population with genetic immune disease. This has enabled large scale studies of the natural history, outcomes, and optimal treatments of these rare defects and continual opportunities for extensive collaborative research.

Benjamin Chen received his MD from Weill Medical College of Cornell University and PhD from Rockefeller University in New York. He conducted his postdoctoral training in the Department of Biology at the Whitehead Institute for Biomedical Science at Massachusetts Institute of Technology in Cambridge, MA. He is currently an Associate Professor of Medicine/Infectious Diseases at the Icahn School of Medicine at Mount Sinai in New York. He is a recipient of the NIH/NIDA Avant Garde Award for innovative HIV research and is a Burroughs Wellcome fund Investigator in the Pathogenesis of Infectious Disease. He is actively involved with the MD-PhD program as an assistant director and is graduate mentor associated with the Immunology and Microbiology graduate training areas. His research has explored the interface between immune cell biology and virology that allows HIV-1 to maintain a persistent infection. Research Interests Mechanisms of HIV-1 virological synapse formation Dr. Chen’s lab is interested in HIV-2 virological synapses, infectious structures formed between human immunodeficiency virus-infected T cells and uninfected CD4+ T cells called virological synapses. Live confocal imaging studies from his laboratory studying fluorescent viral clones revealed a dynamic ordered process of cell-cell adhesion and the active recruitment of viral proteins at these structures. His group has also helped to   30

characterize how the viral membrane fusion process is controlled during infection through virological synapses. Immune evasion through infection by T cell virological synapses Dr. Chen’s lab also discovered that neutralization of HIV-1 infection by patient antibodies is more difficult when the infected cells are mixed with target cells, as compared to infection through cell-free virus particles. The relative resistance to neutralization could be observed with both patient sera as well as with monoclonal antibodies. The laboratory was the first to indicate that the resistance is likely to be due to conformational masking mechanism that is coordinated with cell-to-cell transmission of HIV. Parenteral Transmission of HIV and the movement of infected cells in humanized mice Using humanized mouse models, the Chen lab has been studying the efficiency with which cell-free and cell-associated HIV-1 becomes established in lymphoid tissues during parenteral HIV transmission. Ongoing studies are testing whether the spread of virus within lymphoid tissues is through occurs in spatially restricted clusters or through a diffuse cloud of plasma virions. Intravital imaging studies have been characterizing the movement of infected T cells in humanized mice and explanted lymphoid tissues.

Human Immune Monitoring Center 31

The

Human

Immune

Monitoring

Center

(HIMC)

was

established three years ago within the Tisch Cancer Institute at Mount Sinai as a core service to support cancer trials. It has since grown into a shared resource available to the Immunology Institute members and to members of the Icahn School of Medicine at Mount Sinai. Goals 1. To provide a comprehensive assessment of the immune status in patients. 2. To discover immune profiles of disease, leading to new biomarkers of diagnosis, prognosis, and response to therapy. 3. To quantitate immune responses and help optimize drug dose, delivery, schedule, and combinations. 4. To identify immunomodulatory effects of novel drugs in clinical trials. 5. To develop and implement novel technology that will expand and strengthen our ability to probe immune cell function in humans. Team Drs. Merad and Gnjatic co-direct the Immune Monitoring Center. Dr. Gnjatic is an expert in defining antibody, and CD8+ and CD4+ T cell responses to tumor associated antigens using state-of-the-art technologies, and has considerable experience implementing these approaches for quantitative and qualitative assessment of immunotherapy trials. Dr. Merad is an expert in myeloid cell biology whose work established many phenotypic and functional roles of monocytes, macrophages, and dendritic cells in the periphery and in the tissue microenvironment. The

32

team also includes a Facility Director, Dr. Seunghee KimSchulze, a Clinical Research Coordinator, a Regulatory Affairs Specialist, and four Research Technicians. Services and Platforms The HIMC team helps define optimal project-specific immunologic assessment and implements innovative approaches with a high degree of quality control and reliability. Together with the investigator, the HIMC defines the endpoints and parameters of immune assays, sample and processing requirements (collection, labeling, storage, handling, and shipping), reagents and controls, data analysis, data management expectations and estimated costs. The research environment includes several small adjacent lab spaces, a flow cytometer, laminar hoods, freezers and liquid nitrogen storage, and automated instrument platforms for ELISA and RNA isolation, with all methods and procedures handled by validated SOPs. The HIMC team also assists with grant writing by providing templates for immunological correlates, budget details, and letters of support to accompany the grant application. State-of-the-Art Assays The HIMC offers state-of-the-art immune assays including: 1. Detailed immunophenotyping of lymphoid and myeloid immune cell subsets circulating in the blood or residing in tissues by flow and mass cytometry and immunohistochemical analyses, 2. Detailed analysis of humoral immune responses from plasma or serum using Multiplex, ELISA and seromics,

3. Antigen-specific T cell assays ex vivo or after in vitro sensitization using ELISPOT, intracellular staining of cytokines, CD154-selection, CFSE-based proliferation assays for Treg function, and cytokine detection via Multiplex assay. 4. Semi-automatic nucleic acid isolation from purified cell populations isolated from the blood or tissues, 5. Genome and transcriptome profiling using next generation sequencing of purified immune cell populations in collaboration with the Genomic Core at Mount Sinai. In addition, we would like to highlight the acquisition and implementation of two novel platforms: Mass Cytometry: CyTOF Mass Cytometer (DVS Sciences) is a multiparametric biological analyzer, similar to flow cytometry except that it operates based on time-of-flight mass cytometry. Using antibodies tagged with various heavy metal ions, over 80 parameters can be analyzed simultaneously in a single tube at a high acquisition rate without the need for compensation. We have supported the acquisition of a Mass Cytometer by the School, and are developing and standardizing comprehensive immunophenotyping panels for CyTOF in collaboration with the Flow Cytometry Research Facility. Seromics: Seromics is an exploratory, hypothesis-generating platform that allows the testing of thousands of human proteins simultaneously as potential targets of autoantibodies from patient serum or plasma. The method only requires a few microliters of material, and may be customized for applications other than IgG antibody detection. It is ideally suited to comprehensively look for serum antibody changes at the antigen-specific level following interventions such as immunotherapy, vaccine, chemotherapy, or radiotherapy.

33

Alternatively, the seromic platform can be used to define biomarkers or sets of antigens present at baseline in specific patient populations, which in turn could be used as prognostic or predictive markers. Achievements The HIMC is currently engaged in 21 active clinical trials or studies and has contributed to the immunomonitoring plan of a number of grant applications, of which 18 have already been funded for a total of nearly $16 million, generating substantial indirect costs for the Icahn School of Medicine. The HIMC supports studies in cancer (tumor immune responses, immune monitoring of antitumor therapies), cardiovascular disease (gene therapy trial, role of monocytes in cardiac disease), food allergy (mechanisms of disease), genetics (disease pathogenesis), IBD (mechanism of disease), infectious disease (influenza-induced immune response), ophthalmology (biomarkers of dry eye disease), pediatrics (vaccine-induced immune reactions), and psychiatry (immune targets of depression). We currently have several contracts with pharmaceutical and biotech companies. These include Pfizer (immunomodulation of new drug), Imclone (new target of disease), Dendreon (immunomodulation of new drug), Genentech (immunomodulation of new drug), Immune Design (cancer vaccines), Advaxis (cancer vaccines), Janssen R&D (biomarker study). We expect the number of such interactions to grow, allowing for additional budgetary income from our operations. In addition, we are partnering with industry for implementation of novel technologies such as TCR sequencing (Adaptive Biotech), which will be offered as part of our roster of assays.

Future Our near future goal is to remain at the forefront of technology development by introducing novel assays, methods, and instruments that expand the scope of immune analyses. Such investment is crucial for providing the best means to dissect immune dysregulation in patients and to discover new disease targets. There is accumulating evidence that immune responses are compartmentalized and that circulating cells do not always capture the immune events that occur at the tissue site. Yet most technology efforts have focused on immune analysis of circulating blood cells and many assays are not adapted to characterize tissue immune infiltrates. We plan to build a tissue immune contexture platform for “in situ Immunology” that will help assess the nature, dynamics and molecular characterization of the immune cells that infiltrate human tissues. This platform will be centered on:

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1. Gene expression profiling, including sequencing of the T cell and B cell receptor repertoire; 2. Mass cytometry analysis of tissue infiltrating immune cells using CYTOF or ICP-MS; 3. Detailed multi-fluorescent confocal microscopy using our recently acquired multi-color laser scanning confocal imaging; 4. Definition of biomarkers with clinical value from formalinfixed paraffin-embedded tissues using automated slide stainers and imaging software. The large array of results from HIMC technologies will require data integration. We plan to take advantage of the computing and data center at Mount Sinai, which offers several computational resources.

Sacha Gnjatic received his PhD in Immunology from the University of Paris VII in France. He conducted his postdoctoral training at the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center in New York, NY, where he went on to eventually become an Associate Member. He is currently an Associate Professor of Medicine / Hematology Oncology at the Icahn School of Medicine at Mount Sinai in New York. He is also the Associate Director of the Human Immune Monitoring Center at Mount Sinai. He is a member of the Scientific Advisory Board of several cancer vaccine and immunotherapy programs (Broad Institute, NCI CITN, Boehringer-Ingelheim, Janssen R&D), as well as an Adjunct Associate Professor at Roswell Park Cancer Institute in Buffalo, NY. Dr. Gnjatic also serves on the editorial boards of Cancer Immunity, Cancer Immunology Research, and Frontiers in Immunology. Research Interests The search for specificity: Antibody and T cell responses to tumor antigens Dr. Gnjatic’s lab specializes in the characterization of serological and cellular immune responses against tumor antigens such as NY-ESO-1, p53, MAGE-A3, for their capacity to induce immune responses both spontaneously and in the setting of cancer immunotherapy. Dr. Gnjatic also pioneered large-scale seromic profiling using high-density protein arrays to find biomarkers and new targets of tumor immunity.

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Profiling immune responses in cancer immunotherapy As part of the Cancer Vaccine collaborative and in collobaration with industry, Dr. Gnjatic and his laboratory have participated in the immune monitoring of more than 1800 patients across 50 tumor immunotherapy clinical trials, including cancer vaccines and checkpoint blockade inhibitors. Recently, Dr. Gnjatic designed and analyzed results from a human vaccine based on NY-ESO-1 long overlapping peptides that showed the highest immunogenicity compared to all NY-ESO-1-based vaccines tested to date, and demonstrated the respective role and importance of immunological adjuvants poly-ICLC and montanide. Regulation of immune responses and immunotherapy Beyond the definition of immune responses to cancer, Dr. Gnjatic’s lab also asks how therapies work and why they may fail. Areas of research include 1) Mechanisms of antigen presentation to T cells, such as defining epitopes, evaluating viral, bacterial, and parasitic vectors, cross-presentation of antigen to HLA class I, and endogenous antigen presentation to HLA class II; 2) Impact of immunoregulation on tumor antigen-specific responses, from co-inhibitory molecules expressed on T cells at the tumor site to the effect of regulatory T cells on anti-tumor effectors; and recently 3) Importance of the microenvironment and immune contexture in the tumor, with implementation of immunoscore analyses and correlations with markers of suppression and presence of tumor antigens.

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Immunotherapy

The

Immunotherapy program encompasses an integrated

multidisciplinary effort with primary focus in the areas of food allergy, immune deficiency, immune based disease, and cancer. The Jaffe Food Allergy Institute, founded in 1997, researches the mechanisms underlying food allergy and develops immunotherapeutic approaches to induce tolerance to allergic reactions against milk, egg, peanut and wheat. The Immunodeficiency Clinic at Mount Sinai, treats patients with primary immunodeficiency diseases and common variable immunodeficiency (CVID) and oversees the design of therapies to restore immune dysfunction in these conditions. The Cancer Immunotherapy program, was formally established in 2013 under the auspices of the Tisch Cancer Institute. Goals 1) Translate innovative preclinical models into high impact clinical trials. 2) Develop novel vaccines and cell-based immune therapies for the treatment of cancer, infectious diseases and autoimmune diseases. 3) Provide a dedicated, controlled space to manufacture human therapeutics for Phase I and II clinical trials in accordance with current Good Manufacturing Practice (cGMP) as required by the FDA. 4) Provide a dedicated space for treatment and clinical research Team Dr. Nina Bhardwaj has made seminal contributions to human dendritic cell biology, specifically with respect to their isolation,

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biology, antigen presenting function, and use as vaccine adjuvants in humans. Together with Dr. Merad, Dr. Bhardwaj co-leads the Cancer Immunology Program, which interfaces closely with Immunology Institute. She is the Director of Immunotherapy and also heads the Cancer Immunology Steering Committee of the AACR. She has overseen more than a dozen investigator initiated immunotherapy trials and is also Medical Director of the Vaccine and Cell therapy Facility. Drs. Rachel Sabado and Marcia Mesek are the Vaccine and Cell Therapy Facility Director and QA/QC managers, respectively. Dr. Sabado has had oversight of >30 studies and was involved in the preparation of over 600 individual vaccines for patients with melanoma, glioblastoma, breast cancer, ovarian cancer and pediatric tumors. Marcia Meseck, PhD, Assistant Professor, Dermatology is the QA manager for the Vaccine and cell Therapy facility and the Human Immune Monitoring Core (HIMC) and brings >20 years of experience to the facility. Dr. Hugh Sampson oversees the Jaffe Food allergy Institute, which comprises over 60 members and sees more than 6000 patients per year. Dr. Sampson’s research interests focus on food allergic disorders, the pathogenesis of food-induced anaphylaxis, characterization of allergenic food proteins and their processing by the immune system, genetics of food allergy, and development of mechanisms of immunotherapeutic strategies for treating food allergies including the potential use of biologics, such as anti-IgE and anti-cytokine monoclonal antibodies. Dr. Charlotte Cunningham Rundles is the Director of the Immunodeficiency Clinic, which sees pediatric and adult patients with many forms of known or suspected immunodeficiency, and investigates primary defects of human B

cells, the causes, treatments and outcomes. She oversees a large referral base for patients, that have enabled large scale studies of the natural history, outcomes, and optimal treatments of these rare defects. She is the Director of the Therapeutic Infusion Center for biologic therapy for immunebased diseases. Dr. Miriam Merad and Sacha Gnjatic co-direct the human Immune Montioring Center. Dr. Gnjatic is an expert in defining and developing approaches to assess antibody, CD8+ and CD4+ T cell responses to tumor associated antigens. Dr. Merad is a pioneer in the evaluation of myeloid lineage subsets including monocytes, macrophages and dendritic cells. Dr. Thomas Moran is the Director of the Center for Therapeutic Antibody Development (CTAD). He oversees the technology to produce human monoclonal antibodies using both mouse models and human cells. Resources The Vaccine and Cell Therapy Facility, the Human Immune monitoring Core (HIMC), the Center for Therapeutic Antibody Development (CTAD), and the Therapeutic Infusion Center provide the necessary infrastructure to meet the multidisciplinary needs of Immunology Institute (II) members. The Vaccine and Cell Therapy Facility is a dedicated facility for the manufacture of immune therapies. It has the capacity to prepare vaccines and cellular immunotherapies in a dedicated, controlled space in accordance with current Good Manufacturing Practice (cGMP) regulations as required by the

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US Food and Drug Administration (FDA). This cGMP laboratory features four class 10,000 (ISO 7) cleanrooms, with a Panasonic isolator, biosafety cabinets, cell counters, microscopes, Clinimacs cell separator, incubators, liquid nitrogen storage and controlled rate freezers. It has been designed with the flexibility to manufacture virtually any type of therapy that uses manipulated human cells. The Center for Therapeutic Antibody Development (CTAD) is a state of the art facility for the production of monoclonal antibodies. The facility is completely automated with Hamilton/Stem Cell clone picking robot (ClonaCell EasyPick STAR Robotic System), automated ELISA washing and reading, Octet analyzer for marker free analysis of binding and affinity measurements Intellicyt high throughput 5 color flow cytometer, Luminex multiplex ELISA analyzer and a state of the art electroporation unit for animal DNA immunization. The staff is 7 persons in addition to Dr. Moran, two assistant professors and 5 research associates with advanced degrees. Dr. Aneel Aggarwal, an internationally recognized crystallographer advises on protein production and purification. Therapeutic Infusion Center. Mount Sinai treats a number of patients who need regular infusions of immune globulin for immunodeficiency, autoimmunity, or neurologic disease. The growing number of monoclonal antibody therapies available for inflammatory bowel disease, rheumatoid arthritis, lupus, polymyocytis, gout, post renal transplant, and the autoimmune blistering diseases, provided the impetus to expand our activities. The Therapeutic Infusion service was consolidated and moved to a new larger space in the Hess Building in April 2013. This resource is directed by Dr. Cunningham-Rundles with its own staff, and a dedicated pharmacy. This space is also used for

investigational studies such as mepolizumab for eosinophilic syndromes and polyclonal anti RSV immune globulin in a safety study. Achievements 1. Cancer immunotherapy. Drs Bhardwaj, Brody, Gnjatic, Merad, and Sikora apply combinations of unique immune modulators, novel vaccines, adoptive cell therapies and checkpoint blockade inhibitors to treat cancers. The Cancer Immunology program brings in revenues of more than 10 million dollars for a total of 61 projects that encompass preclinical and clinical research. Selected examples of ongoing clinical trials are listed in Appendix IV. Immune modulators: TLR agonists, also referred to as pathogen associated molecular patterns (PAMPs) are potent activators of DC and lead to the induction of strong antigen-specific T cell responses in vivo. II program members have: • Iteratively tested TLR agonists and identified CpG and polyICLC as the most potent adjuvants for the induction of tumor-specific immunity • Developed a novel vaccine strategy comprising whole irradiated tumor cells co-delivered with TLR agonists as an effective immunogen • Adapted this technology to create GMP grade cell-based vaccines in the Vaccine and Cell Therapy Facility for application to solid tumors • Developed a successful clinically active in situ “autovaccination” approach that combines low dose radiation and injection of a TLR agonist directly into the same tumor site to activate tumor infiltrating DC and promote tumor specific T cell immunity • Combined in situ auto-vaccination with intratumoral “Flt3L” 39



which recruits and promotes the survival of intratumoral DC to improve the in situ vaccine approach Demonstrated feasibility and efficacy of intratumoral therapeutic vaccination with Poly-ICLC of advanced multiple solid tumors

Vaccines: II members are testing novel vaccine formulations in the clinic, including unique antigen formulations, dendritic cell based vaccines and antigen-expressing bacterial vectors. Their achievements include: • Application of promising antigen formulations (long peptide formulations, viral vectors) to induce strong integrated immune responses in patients with ovarian cancer and melanoma • Development of potent dendritic cell vaccines that induce strong immune responses in vivo • Determination that DC vaccines actually function as vehicles for antigen rather than directly priming T cell immunity and are cross-presented by endogenous DC • Use of systemic immune modulators to improve crosspresentation of DC vaccines by endogenous DC • Testing cytokines such as IL-7 in combination with DC based vaccines (Provenge) in prostate cancer to improve immunity • Mobilizing and targeting DC in situ with Flt3-L and antigenDEC-205 antibody conjugates • Testing attenuated Listeria vectors bioengineered to secrete HPV16 E7 protein in Head and Neck cancers in the neoadjuvant setting Checkpoint blockade inhibitors: Monoclonal antibodies that reverse immune exhaustion (eg anti-CTLA-4, anti-PD-1 and antiPDL-1) have shown dramatic tumor regression in solid tumors. II members are combining these agents with other modalities to

improve their efficacy. They have: •

• • •



Demonstrated that the combination of anti-CTLA-4 (Ipilimumab) and cytoxan (to reduce T regulatory cells) in metastatic melanoma unexpectedly aggravates autoimmune side-effects. This significant observation urges re-examination of the effects of cytoxan on T regulatory function in vivo Conducted studies to test the combination of anti-CTLA-4 with Provenge vaccine in prostate cancer Conducted studies to test anti-CTLA-4 or anti-PD-1 in combination with HSV oncolytic virus (T-vec) Planned participation in a first of its kind multicenter, phase I, open label study combining ipilimumab with three different formulations of poly IC:LC/NY-ESO-1/Montanide vaccines Planned participation in a multicenter, CVC-sponsored Phase 1 study of a MEDI4736 (anti-PDL-1) and tremelimumab combination, in 6 disease-specific cohorts. This exciting combination is expected to synergistically impact tumor growth

Adoptive cell therapies (ACT). ACT approaches are proving to have great impact in T and B cell malignancies. Immunology Institute members are exploring these approaches in hematological malignancies. They have: • Identified two cancer-associated genes that are commonly expressed in myeloma cells, and associated with progression of disease and proliferation (the type I Melanoma Antigen GEnes (MAGE) CT7 (MAGE-C1) and MAGE-A3) • Shown that vaccination with MAGEA3 and TLR agonists efficiently primes humoral and adaptive immunity in patients pre-transplant • Determined that adoptive transfer of tumor antigen primed PBMC post-transplant maintains immunity 40

2. Immunotherapy for Food Allergy. Drs Sampson, Berin and Li have used a variety of immunotherapeutic approaches to treat food allergies. As examples, they have: • Demonstrated that heat-denatured (baked) forms of milk or egg are tolerated by a majority with those allergies and that introduction of baked- milk/egg products into the diet of those milk/egg allergic children accelerates the development of full tolerance to all forms of these foods • Conducted studies of novel therapies using ingredients from traditional Chinese medicine • Developed a novel food allergy vaccine using engineered mutated peanut proteins • Conducted the first placebo-controlled study of egg oral immunotherapy • Conducted the first placebo-controlled trial of dual therapy (immunotherapy and anti-IgE) • Conducted the first placebo-controlled trial of anti-IgE (TNX-901 & omalizumab) for food allergy that heatdenatured (baked) forms of milk or egg are tolerated by a majority with those allergies and that introduction of bakedmilk/egg products into the diet of those milk/egg allergic children accelerates the development of full tolerance to all forms of these foods • Conducted studies of novel therapies using ingredients from traditional Chinese medicine and also developed a novel food allergy vaccine using engineered mutated peanut proteins. • Conducted the first placebo-controlled study of egg oral immunotherapy, of dual therapy (immunotherapy and antiIgE) and of of anti-IgE (TNX-901 & omalizumab) for food allergy. 3. Monoclonal

Antibody

Development.

The

Center

for

Therapeutic Antibody Development (CTAD) provides program members with the capability to produce antibodies against unique immunological targets. The CTAD is invested in bringing monoclonal antibodies that have potential to impact cancer and autoimmunity into the clinic. The CTAD has: • • • • •

Produced monoclonal antibodies for the community for over 15 years Submitted two invention disclosures describing new technology for mAb production Licensed 15 new antibodies to commercial entities Generated more than 3 million dollars in antibody earnings over the last 10 years Formed partnerships and collaborations with USDA-Plum Island, Columbia University, Mass General Hospital, Vaxinnate Corporation, and MRC-Tech, London in addition to internal collaborations

Future Improving the immune therapy platform • Advance a Personalized Vaccine Program based on genomic sequencing of individual cancers in conjunction with the Genomics Institute leadership • Establish adoptive T cell therapy platforms to treat cancer and autoimmunity • Develop platforms to generate chimeric antigen receptor expressing T cells • Integrate emerging novel immunotherapeutic approaches with chemotherapeutic and biological therapies in the treatment of cancer • Apply in house inventions to prepare oncolytic viral vectors to treat tumors (Newcastle Disease Virus) • Improve the quality of transplants by using leukapheresis-

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derived hematopoietic progenitor cells Programmatic Development • Increase investigator initiated studies • Identify molecular, epigenetic and immune cellular signatures in the TME that provide predictive and prognostic data for immunotherapy • Interface with national organizations to bring new interventions to ISMMS • Develop and strengthen interactions of the Immunology Institute with the Experimental Therapeutics Institute now led by Dr. Paul Kenny.

Nina Bhardwaj received her undergraduate training from Wellesley College and completed her M.S., M.D., and Ph.D. training at New York University School of Medicine. Following an internship and residency in Internal Medicine at Brigham & Women’s Hospital, she trained at the Hospital for Special Surgery (Rheumatology) and The Rockefeller University (Immunology). Dr. Bhardwaj is currently a Professor of Medicine and Director of Immunotherapy at the Icahn School of Medicine at Mount Sinai. Research Interests Antigen presentation Dr. Bhardwaj’s Lab studies mechanisms by which human DCs acquire and process antigens derived from apoptotic cells. Her team has identified receptors utilized by DCs to phagocytose apoptotic cells, which either modulate DC immunity through the production of immunoevasive c y t o k i n e s , and others that promote immunity. Dr. Bhardwaj’s lab recently identified a new receptor for apoptotic cells, CD44, that imparts an inhibitory signal to DCs and which is being investigated as a tolerogenic target in vivo. The mechanistic basis of interaction between human DCs and viruses Although DCs exhibit high sensitivity in detecting pathogens; the fact that DCs are present in extremely low numbers in

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the body has made it difficult to understand their biology in HIV infection. Dr. Bhardwaj’s lab recently demonstrated that HIV activates DCs through TLR7. High-throughput microarray analysis is being used to gain insights into the global genomic changes that occur in DC subsets in response to HIV. In particular, the team is focusing upon TLR, RIG-I and infllammasome pathways to understand how HIV may affect DC function. Pathogenesis of human disease Dr. Bhardwaj’s lab focuses on subjects with melanoma and other cancers. They undertake genomic approaches to investigate the consequences of chronic inflammation and to identify pathways that drive oncogenic progression. Dr. Bhardwaj’s lab has also used state of the art immune monitoring and genetic approaches to analyze the changes in the immune response to infection and to metastatic disease. Immunotherapy Dr. Bhardwaj’s lab has undertaken several trials in melanoma and other cancers that are based upon potentiating the immune activating potential of dendritic cells. These have resulted in the generation of significant immune responses, w h i c h in some cases correlated with clinical outcome. This program has been expanded to subjects with brain, breast, p r o s t a t e , pancreatic and ovarian cancer. Additional vaccine platforms include adjuvants that target DCs in vivo as well, including TLR agonists and bacteria or virus based vector approaches.

Thomas Moran received his PhD from Boston University working with Drs. Vinay Kumar and Michael Bennett studying immunological response to organ transplant in small and large animal models followed by postdoctoral training in the laboratory of Dr. Hans Wigzell at the University of Uppsala, Sweden before returning to the US and the Department of Microbiology at Mount Sinai School of Medicine. Dr. Moran has published widely on immunity to virus infection using both mouse models and studies in human subjects. He served as the overall director of the NIH funded Center for Investigating Viral Immunity and Antagonism (CIVIA) that focused on studies of human immunology and infectious disease by advancing technological methodologies, supporting inventive research, serving as a conduit for collaboration and promoting exchange of scientific information. Among other projects CIVIA profiled the immune response of patients receiving the live-attenuated influenza virus vaccination (JID 2013). Dr. Moran served as the PI for the Viral Immunity in Pregnancy study (VIP) that analyzed changes that occur in women during pregnancy with an emphasis on understanding the enhanced susceptible to infection (JCI 2012). Currently in addition to his research interests Dr. Moran is the Director of the Center for Therapeutic Antibody Development (CTAD) here at Mount Sinai School of Medicine.

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Research Interests Program for Research Experimentation (PRIME)

on

Immune

Modeling

and

The project encompasses several research centers working in collaboration. In the interdisciplinary center at Mount Sinai School of Medicine PRIME has been actively mapping the regulatory network in viral infected dendritic cells by analyzing experimental data. Using this network, models and simulations have been developed to further our understanding of the innate immune response (J. Virology 2012). Innate immune factors influencing bacterial coinfection in influenza virus infected subjects The Moran laboratory is currently studying the role of innate cytokines released in response to influenza virus on the growth of coinfected Streptococcus pneumonia. Evidence suggests that the interaction between type 1 interferon and IL17 may be a crucial relationship that influences outcome (J. Virology 2012) Center for Therapeutic Antibody Development (CTAD) A number of collaborative projects are in progress aimed to develop monoclonal antibodies with therapeutic applications. Technology has been developed and is currently being used by CTAD to produce human monoclonal antibodies using both mouse models and human cells. Collaborations are ongoing with many of the Immunology Institute members (PNAS 2012).

Joshua Brody received his MD from SUNY Stony Brook School of Medicine and subsequently trained in Internal Medicine at Yale New Haven Hospital. He conducted post-doctoral training in the lab of Ed Engleman at Stanford University followed by a clinical fellowship in medical oncology and additional post-doctoral research in the lab of Ronald Levy. He is currently an Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai in New York and Director of the Lymphoma Immunotherapy Program.

tumor-antigen-loaded DC for presentation to anti-tumor T cells. Pre-clinical modeling has demonstrated the efficacy of the approach and a phase I/II clinical trial was initiated in 2014. The first patients have completed therapy and demonstrated recruitment of BDCA1 and BDCA3 subsets to the tumor, activation of DC and T cell subsets, as well as tumor regressions at untreated tumor sites including lymph node, bone marrow and peripheral blood and appears to spare normal B cells while eliminating malignant B cells. Additional pre-clinical mechanistic studies are in progress while patient recruitment is ongoing.

Research Interests

Dr. Brody’s prior work assessed the ability of anti-tumor T cells to be selectively amplified and activated by transfer to the lymphodepleted host. Pre-clinical modeling demonstrated that such an ‘immunotransplant’ maneuver yielded greater antitumor efficacy compared to vaccination alone. A phase I/II clinical trial for patients with higher grade (mantle cell) lymphoma confirmed that the maneuver amplified tumorreactive T cell responses in comparison to vaccination alone. The Brody Lab has now shifted the focus to priming anti-tumor immune responses using checkpoint blockade antibodies (e.g. anti-CTLA-4 and anti-PD-1) and shown that immunotransplant can increase the anti-tumor effect of these therapies. Mechanistic pre-clinical studies have shown that transfer to the lymphodepleted host has potent effects on the signal transduction of activated T cells and their modulation by checkpoint blockade. An early phase clinical trial is being developed for patients with melanoma, multiple myeloma and aggressive lymphoma.

Flt3L-primed In Situ Vaccination for Lymphoma in Mouse and Man Dr. Brody’s lab has developed a novel therapeutic vaccine based on prior work while at Stanford initially using intratumoral administration of a TLR9 agonist to convert malignant B cells into ‘amateur’ antigen presenting cells. That work progressed from pre-clinical modeling to a series of clinical trials for patients with low-grade lymphoma showing that the approach could induce anti-tumor T cells and clinical remissions, some lasting for years. The new approach seeks to induce more powerful anti-tumor T cell responses by utilizing ‘professional’ antigen presenting cells, i.e, dendritic cells (DC) by combining: 1) intratumoral administration of Flt3L to recruit DC, 2) lowdose radiotherapy to release/load tumor antigens, and 3) intratumoral administration of a TLR3 agonist to activate

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Immunotransplant for lymphoma and solid tumors

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Education

When the Immunology Institute was created in 2007, a central objective of the Institute was to educate and train the next generation of immunologists. A key component of this objective is the development of a PhD training program dedicated to immunology. Prior to 2007, PhD students training in immunology labs were part of a big umbrella training area known as Mechanism of Diseases and Therapy (MDT) and there was no formal training in immunology as a discipline. Thus in 2007, the creation of a separate training area for Immunology was proposed by the leadership of the Institute and was approved by the Graduate School. The curriculum that developed encompasses basic courses in molecular, cellular and system biology in the first year, which then progresses to immunology-specific courses starting the second year. Goal The goal of the IMM training area is to provide students interested in immunology with a rigorous and flexible program. Students will be given the individual intellectual and technical skills required to become outstanding scientists in the field of immunology. By bringing students in various immunology labs into a single training area, the students get together at least twice a week for educational activities. In addition to the educational objectives, these forums also enable the exchange of scientific ideas and knowledge amongst the students. Team The IMM training area is led by two Co-Directors, Dr. Adrian Ting and Dr. Konstantina Alexandropoulos. One of the CoDirectors will chair the qualifying and thesis proposal exams of all IMM students. Through this arrangement, the Co-Directors keep fully abreast of the progress of each individual student. The Co-Directors are assisted by a Steering Committee that consists

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of 6 other faculty plus two student representatives. The role of the Steering Committee is to provide suggestions and advice to the Co-Directors to enhance the training and educational experience of the IMM students. Program The course requirements include the basic Biomedical Sciences I and II courses as well as a minimum of two immunology courses: Fundamentals in Immunology (Fall semester) and Advanced Topics in Immunology (Spring semester). In Fundamentals in Immunology students will get a general yet in depth overview of the immune system through a lecture based course. Several faculty members with different expertise in specific areas of Immunology participate in the course. The Advanced Topics in Immunology course that follows the Fundamentals course will offer students a guided discussion class that reviews current literature in three major areas of immunology. The Advanced Topics course will cover different materials every year and students who wish to take this course more than once are free to do so. Laboratory rotations and research training allows students to rotate and select any of the multiple laboratories that are currently working in immunology, which include allergy, immunology of infectious disease, inflammation, immunodeficiency, autoimmunity, mucosal immunity and transplantation among others. Research groups in the Immunology Institute are using multiple approaches and different model systems to understand how the immune system works, how it is regulated and its function is defective in the context of disease. Numerous laboratories are working in close collaboration with the Mount Sinai Hospital and clinical investigators to develop a clear understanding of the role of the immune system in various diseases with a focus on translational research.

Students will also participate in an Immunology Journal Club, Work in Progress and Seminar Series. The Journal Club will provide the means for students to interact with each other in a small scientific forum. During Work-in-Progress, their work will be evaluated and critiqued by their peers, which include other students, postdocs and faculty members from the Immunology Institute. The seminar series will give them the chance to bolster their knowledge of immunology through a formal seminar with invited speakers as well as an informal lunch session with the speakers. Students in the immunology training area will also be encouraged to participate in the training activities of other

multidisciplinary training areas with overlapping interest such as those in Microbiology, Cancer Biology, Genetics and Genomic Sciences. Similarly, students from all the training areas are welcome to participate in any of the immunology training activities. After completing the immunology training program students will be prepared to continue their careers in basic and/or translational research, and will be able to compete effectively for the best postdoctoral training opportunities in both academia and industry.

Curriculum Year 1 Fall Biomedical Science I (BSR1001) Biostatistics (BSR1010) Responsible Conduct of Research (BSR1003) Introduction to Journal Club I (BSR1004) Laboratory Rotation (BSR1006) MTA (BSR 5004)

Spring Biomedical Science II (BSR1002) Introduction to Journal Club II (BSR1005) Translating Science Laboratory Rotation (BSR1007) MTA (BSR5004)

Year 2 Fall Spring Fundamentals of Immunology (BSR1501) Advanced Topics in Immunology (BSR6502) Immunology Journal Club (BSR4501) Immunology Journal Club (BSR4501) Immunology Seminar Series (BSR5501) Immunology Seminar Series (BSR5501) Dissertation Research Dissertation Research General Knowledge Exam 3 Credits of advanced electives (anytime Yr 2-3) Thesis Proposal Exam Year 3 Fall Spring 47

Immunology Journal Club (BSR4501) Immunology Seminar Series (BSR5501) Dissertation Research

Immunology Journal Club (BSR4501) Immunology Seminar Series (BSR5501) Dissertation Research Fundamentals in Immunology

Immunology Course Directors: Fundamentals of Immunology: Dr. Konstantina Alexandropoulos Adv. Topics in Immunology: Dr. Patricia Cortes Seminar Series, which includes Immunology Seminars and Work in Progress: Dr. Julie Blander Journal Club: Drs. Garabet Yeretssian and Adrian Ting Steering Committee Faculty Konstantina Alexandropoulos Julie Blander Patricia Cortes Peter Heeger Sergio Lira Miriam Merad Adrian Ting Karen Zier Student representatives Noa Simchoni Erica Weinstein Courses

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This is a comprehensive introductory course to cellular and molecular immunology. It is taught by several faculty members with expertise in different aspects of Immunology and is updated each year to accommodate increasing knowledge in the field. See Appendix II for the class schedule. Advanced Topics in Immunology The advanced topics course highlights specific areas of immunology for in depth study. This is organized as a series of interactive seminars where students are given current papers to read, present and discuss in a focused fashion. The course consists of three different modules that can be taken together or independently. Students must take Fundamentals in Immunology, or have taken a comparable course, before they can register for Advanced Topics. See Appendix II for class schedule. Immunology Journal Club This course follows an intensive small group discussion format that critically evaluates original research articles in the area of immunology. The articles are selected by the presiding faculty member, and include recent important advances in immunology or investigations that provide conceptual advances relating to long-standing problems. This class is required for students beginning their second year until they successfully pass their thesis proposal exam. First year students

interested in immunology are encouraged Attendance is required for all classes.

to

attend.

Immunology Seminar Series This seminar series features presentations by prominent leaders in the field of Immunology, and is attended by all faculty, postdocs and student members of the Immunology Institute. Speakers are either from the US or abroad. Post-docs and students are strongly encouraged to meet with invited seminar speakers during an informal luncheon scheduled for that day. Students are expected to familiarize themselves with the speaker’s research areas. See Appendix III for seminar schedule. Immunology Work in Progress Seminars This seminar series is conducted on a weekly basis, and provides a forum for both students and post-docs to present their own research work to colleagues and mentors within the Immunology Institute. Students are required to attend all Work in Progress seminars. Students will be required to present a 25minute seminar annually, beginning at the end of their 2nd year. The work-in-progress aspect of the presentation is emphasized and final polished studies are not expected. Students are expected to leave a 5-minute period at the end of their presentation for questions and discussions. Advanced Immunology Boot Camp All the students are required to attend the Advanced Course in Immunology offered by the American Association of Immunologists. This is a one-week intense and rigorous course that students take during the summer after their second year in the program.

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Immunology Institute Retreat Members of the Immunology Institute including faculty, students and postdoctoral fellows meet at an off-campus venue for a day during the fall semesters to interact scientifically and socially within an informal setting. Several students and postdocs give oral presentations following selection of their abstracts by screening faculty, whereas all participating students are required to present posters describing their current research. Achievements From its inception in 2007 to June 2014, 17 students will have defended their PhD theses. 8 of these students were in the PhD track and 9 were in the MSTP track. Currently, there are 18 students in the program consisting of 11 in the PhD track and 7 in the MSTP track. Our PhD students have published first-author papers in JI, JEM, JCI, Immunity, Nature Immunology, Nature Medicine, Nature and Cell. Future Over the last 7 years, the quality of our graduate students have steadily improved, in line with the improvement we have seen institutional wide. We aim to make IMM an even more competitive program by recruiting outstanding candidates. We are also developing 'specialized concentration' areas of study in conjunction with other training areas. For example, in collaboration with the Cancer Biology (CAB) training area, we are developing a curriculum in tumor immunology in which both IMM and CAB students can participate. The goal of this particular interaction is to train PhD students such that they become well versed in both tumor-intrinsic processes leading to

cellular transformation, as well as tumor-extrinsic interaction with the immune system post-transformation. We envision developing more such 'specialized concentrations' with other

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training areas including Microbiology, Genetics and System Biology.

Adrian Ting received his PhD in Immunology from the Mayo Graduate School/Mayo Clinic in Rochester, MN. He conducted his postdoctoral training in the Department of Molecular Biology at Massachusetts General Hospital in Boston, MA. He is currently an Associate Professor of Medicine/Clinical Immunology at the Icahn School of Medicine at Mount Sinai in New York. He has been a Co-Director of the Immunology Training Area for the PhD program since its inception in 2007. He is currently a member of the NIH Cellular & Molecular Immunology-A (CMI-A) study section.

Caspase-8 function's as a survival molecule

Research Interests

Excessive cell death in the gut and skin epithelium results in inflammation. Dr. Ting's lab is studying how TNF and its regulation of CYLD affects inflammation. Since dysregulation of TNF causes inflammatory disorders such as psoriasis and IBD, his lab is currently examining the role of CYLD, RIP1 ubiquitination and cell death in animal models of inflammation. Concurrently, tissues from patients with inflammatory disorders are being examined for dysregulation of these molecular mechanisms of cell death. The goal is to thoroughly characterize the regulation of these cell death pathways so that drugs can be rationally designed to modulate these pathways for therapeutic purposes in inflammatory diseases.

Ubiquitination of RIP1 as a cell death checkpoint Dr. Ting's lab is interested in how ubiquitin modification affects cellular survival and death, and in turn how life and death decisions affect inflammation. One focus of his studies is the role played by ubiquitination of the TNFR1 signaling molecule RIP1. His laboratory made the discovery that non-canonical K63-linked polyubiquitination of RIP1, or the lack thereof, determines whether cell survival or apoptotic cell death ensues in response to TNF.

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More recently, Dr. Ting's lab also discovered that ubiquitination has a major role in regulating an inflammatory form of cell death known as necroptosis. They made the observation that Caspase 8 has a pro-survival function (contrary to its well established role in causing apoptosis) via the cleavage of the tumor suppressor CYLD to suppress necroptosis. CYLD is a deubiquitinase enzyme that removes K63-linked polyubiquitin chains from target proteins including RIP1. Deubiquitination of RIP1 by CYLD is necessary for necroptosis and removal of CYLD by Caspase-8 sustains RIP1 ubiquitination and cell survival. Regulation of inflammation by cell death pathways

Konstantina Alexandropoulos received her Ph.D. in Molecular Biology from the City University of New York (CUNY), USA. She did her postdoctoral training in Dr. David Baltimore’s laboratory at Rockefeller University and Massachusetts Institute of Technology (MIT). After her postdoctoral training she worked for 10 years as an Assistant Professor at the College of Physicians and Surgeons, Columbia University Medical Center. She is currently Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York. She is the co-Director of the Immunology multidisciplinary training area; course Director/Lecturer for Immunology training area-related courses, and Adjunct Lecturer at Drexel University Medical School. She serves in a number of Institutional committees including admissions committees for the MD/Ph.D and Ph.D programs, faculty recruitment committees and Immunology MTA Steering committee. She became elected member of the Henry Kunkel Society in 2013. Research Interests Mechanisms of Central Tolerance and T cell mediated Autoimmunity We are studying the role of medullary thymic epithelial cells (TECs) in establishment of T cell tolerance using conditional knockout mice. We have shown that conditional depletion of mTECs leads to development of autoimmune hepatitis (AIH)

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that recapitulates all known histopathological and immunological characteristics of the human disease (JCI, 2013). We are currently exploring the mechanisms leading to disease development and developing novel therapeutic approaches for managing/treating AIH. Regulation of thymic dendritic cell populations by thymic stromal cells We recently found that in addition to regulating central T cell tolerance, mTECs also control the intrathymic development of specific dendritic cell (DC) subsets as well as recruitment of peripheral DCs into the thymus. We are interested in elucidating the unique and/or overlapping contributions of mTECs and thymic DCs in the generation of the effector and regulatory T cell repertoires in the thymus as well as in peripheral autoimmunity. Role of the T cell repertoire in mucosal inflammation and composition of the intestinal microbiota In recent studies we explored whether disturbances in the T cell repertoire lead to disruptions in mucosal homeostasis. We found that altered T effector and T regulatory cell repertoires resulting from aberrant T cell selection in the mTEC-depleted thymus associate with development of colitis in genetically susceptible mice. This is accompanied by disturbances in the colonic bacterial load and composition suggesting that host genetics (T cell repertoire) can influence host microbiota and regulate mucosal inflammation within the context of an otherwise normal mucosal environment.

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Appendix I Recent publications

APPENDIX I Immunology Institute Faculty Publications (2013-2014) 1.

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Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP, Belkaid Y, Merad M. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science. 2014;343(6178):1249288. Shan M, Gentile M, Yeiser JR, Walland AC, Bornstein VU, Chen K, He B, Cassis L, Bigas A, Cols M, Comerma L, Huang B, Blander JM, Xiong H, Mayer L, Berin C, Augenlicht LH, Velcich A, Cerutti A. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science. 2013;342(6157):447-53. Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL, Clemente JC, Knight R, Heath AC, Leibel RL, Rosenbaum M, Gordon JI. The long-term stability of the human gut microbiota. Science. 2013;341(6141):1237439. Fierer N, Ladau J, Clemente JC, Leff JW, Owens SM, Pollard KS, Knight R, Gilbert JA, McCulley RL. Reconstructing the microbial diversity and function of pre-agricultural tallgrass prairie soils in the United States. Science. 2013;342(6158):621-4. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341(6150):1241214. Suthanthiran M, Schwartz JE, Ding R, Abecassis M, Dadhania D, Samstein B, Knechtle SJ, Friedewald J, Becker YT, Sharma VK, Williams NM, Chang CS, Hoang C, Muthukumar T, August P, Keslar KS, Fairchild RL, Hricik DE, Heeger PS, Han L, Liu J, Riggs M, Ilke DN, Bridges ND, Shaked A. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. The New England Jounal of Medicine. 2013; 369:2031. Agudo J, Ruzo A, Tung N, Salmon H, Leboeuf M, Hashimoto D, Becker C, Garrett-Sinha LA, Baccarini A, Merad M, Brown BD. The miR-126-VEGFR2 54

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axis controls the innate response to pathogen-associated nucleic acids. Nat Immunol. 2014;15(1):54-62. Jojic V, Shay T, Sylvia K, Zuk O, Sun X, Kang J, Regev A, Koller D, Best AJ, Knell J, Goldrath A, Cohen N, Brennan P, Brenner M, Kim F, Rao TN, Wagers A, Heng T, Ericson J, Rothamel K, Ortiz-Lopez A, Mathis D, Benoist C, Bezman NA, Sun JC, Min-Oo G, Kim CC, Lanier LL, Miller J, Brown B, Merad M, Gautier EL, Jakubzick C, Randolph GJ, Monach P, Blair DA, Dustin ML, Shinton SA, Hardy RR, Laidlaw D, Collins J, Gazit R, Rossi DJ, Malhotra N, Kreslavsky T, Fletcher A, Elpek K, Bellemare-Pelletier A, Malhotra D, Turley S. Identification of transcriptional regulators in the mouse immune system. Nat Immunol. 2013;14(6):633-43. Mingueneau M, Kreslavsky T, Gray D, Heng T, Cruse R, Ericson J, Bendall S, Spitzer MH, Nolan GP, Kobayashi K, von Boehmer H, Mathis D, Benoist C, Best AJ, Knell J, Goldrath A, Jojic V, Koller D, Shay T, Regev A, Cohen N, Brennan P, Brenner M, Kim F, Rao TN, Wagers A, Rothamel K, Ortiz-Lopez A, Bezman NA, Sun JC, Min-Oo G, Kim CC, Lanier LL, Miller J, Brown B, Merad M, Gautier EL, Jakubzick C, Randolph GJ, Monach P, Blair DA, Dustin ML, Shinton SA, Hardy RR, Laidlaw D, Collins J, Gazit R, Rossi DJ, Malhotra N, Sylvia K, Kang J, Fletcher A, Elpek K, Bellemare-Pelletier A, Malhotra D, Turley S. The transcriptional landscape of alphabeta T cell differentiation. Nat Immunol. 2013;14(6):619-32. Magri G, Miyajima M, Bascones S, Mortha A, Puga I, Cassis L, Barra CM, Comerma L, Chudnovskiy A, Gentile M, Llige D, Cols M, Serrano S, Arostegui JI, Juan M, Yague J, Merad M, Fagarasan S, Cerutti A. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol. 2014;15(4):354-64. Randolph G, Merad M. Reply to: "Can DCs be distinguished from macrophages by molecular signatures?". Nat Immunol. 2013;14(3):18990. Guermonprez P, Helft J, Claser C, Deroubaix S, Karanje H, Gazumyan A, Darasse-Jeze G, Telerman SB, Breton G, Schreiber HA, Frias-Staheli N,

Billerbeck E, Dorner M, Rice CM, Ploss A, Klein F, Swiecki M, Colonna M, Kamphorst AO, Meredith M, Niec R, Takacs C, Mikhail F, Hari A, Bosque D, Eisenreich T, Merad M, Shi Y, Ginhoux F, Renia L, Urban BC, Nussenzweig MC. Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection. Nat Med. 2013;19(6):730-8. 13. Chow A, Huggins M, Ahmed J, Hashimoto D, Lucas D, Kunisaki Y, Pinho S, Leboeuf M, Noizat C, van Rooijen N, Tanaka M, Zhao ZJ, Bergman A, Merad M, Frenette PS. CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med. 2013;19(4):429-36. 14. Gnjatic S, Bhardwaj N. Antigen depots: T cell traps? Nat Med. 2013;19(4):397-8. 15. Bokulich NA, Subramanian S, Faith JJ, Gevers D, Gordon JI, Knight R, Mills DA, Caporaso JG. Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing. Nat Methods. 2013;10(1):57-9. 16. Ruel J, Ruane D, Mehandru S, Gower-Rousseau C, Colombel JF. IBD across the age spectrum-is it the same disease? Nat Rev Gastroenterol Hepatol. 2014;11(2):88-98. 17. Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol. 2013;13(2):118-32. 18. Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL, Knight R, Beiko RG, Huttenhower C. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol. 2013;31(9):814-21. 19. Muller TD, Muller A, Yi CX, Habegger KM, Meyer CW, Gaylinn BD, Finan B, Heppner K, Trivedi C, Bielohuby M, Abplanalp W, Meyer F, Piechowski CL, Pratzka J, Stemmer K, Holland J, Hembree J, Bhardwaj N, Raver C, Ottaway N, Krishna R, Sah R, Sallee FR, Woods SC, Perez-Tilve D, Bidlingmaier M, Thorner MO, Krude H, Smiley D, DiMarchi R, Hofmann S, Pfluger PT, Kleinau G, Biebermann H, Tschop MH. The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. Nat Commun. 2013;4:1968. 20. Parikh A, Lee C, Peronne J, Marchini S, Baccarini A, Kolev V, Romualdi C, Fruscio R, Shah H, Wang F, Mullokandov G, Fishman D, D'Incalci M, Rahaman J, Kalir T, Redline RW, Brown BD, Narla G, DiFeo A. microRNA181a has a critical role in ovarian cancer progression through the

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regulation of the epithelial-mesenchymal transition. Nat Commun. 2014;5:2977. 21. Knights D, Clemente JC, Nakielny S, Gordon JI, Fierer N, Knight R. Cohabiting family members share microbiota with one another and with their dogs. Elife. 2013;2:e00458. 22. O'Donovan MJ, Maximova OA, Sharma S, Zhu J, Wang H, Morse HC, 3rd, Ozato K. The transcription factor IRF8 activates integrin-mediated TGFbeta signaling and promotes neuroinflammation. Immunity. 2014;40(2):187-98. 23. Shechter R, Miller O, Yovel G, Rosenzweig N, London A, Ruckh J, Kim KW, Klein E, Kalchenko V, Bendel P, Lira SA, Jung S, Schwartz M. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity. 2013;38(3):555-69. 24. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, Garcia-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38(4):792-804. 25. Yoshida Y, Yoshimi R, Yoshii H, Kim D, Dey A, Xiong H, Munasinghe J, Yazawa I, O'Donovan MJ, Maximova OA, Sharma S, Zhu J, Wang H, Morse HC, 3rd, Ozato K. The transcription factor IRF8 activates integrinmediated TGF-beta signaling and promotes neuroinflammation. Immunity. 2014;40(2):187-98. 26. Miller E, Bhardwaj N. A bloody mess: dendritic cells use hemophagocytosis to regulate viral inflammation. Immunity. 2013;39(3):429-31. 27. Farache J, Koren I, Milo I, Gurevich I, Kim KW, Zigmond E, Furtado GC, Lira SA, Shakhar G. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity. 2013;38(3):581-95. 28. Yu CI, Becker C, Wang Y, Marches F, Helft J, Leboeuf M, Anguiano E, Pourpe S, Goller K, Pascual V, Banchereau J, Merad M, Palucka K. Human CD1c+ dendritic cells drive the differentiation of CD103+ CD8+ mucosal effector T cells via the cytokine TGF-beta. Immunity. 2013;38(4):818-30 29. Kwan WH, van der Touw W, Paz-Artal E, Li MO, Heeger PS. Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med. 2013;210(2):257-68. 30. Bongers G, Pacer ME, Geraldino TH, Chen L, He Z, Hashimoto D, Furtado GC, Ochando J, Kelley KA, Clemente JC, Merad M, van Bakel H, Lira SA.

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Interplay of host microbiota, genetic perturbations, and inflammation promotes local development of intestinal neoplasms in mice. J Exp Med. 2014;211(3):457-72 (cover article). Ruane D, Brane L, Reis BS, Cheong C, Poles J, Do Y, Zhu H, Velinzon K, Choi JH, Studt N, Mayer L, Lavelle EC, Steinman RM, Mucida D, Mehandru S. Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. J Exp Med. 2013;210(9):1871-88. Jianjun Y, Zhang R, Lu G, Shen Y, Peng L, Zhu C, Cui M, Wang W, Arnaboldi P, Tang M, Gupta M, Qi CF, Jayaraman P, Zhu H, Jiang B, Chen SH, He JC, Ting AT, Zhou MM, Kuchroo VK, Morse HC, 3rd, Ozato K, Sikora AG, Xiong H. T cell-derived inducible nitric oxide synthase switches off Th17 cell differentiation. J Exp Med. 2013;210(7):1447-62. Berres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, Idoyaga J, Ruzo A, Lupo PJ, Hicks MJ, Shih A, Simko SJ, Abhyankar H, Chakraborty R, Leboeuf M, Beltrao M, Lira SA, Heym KM, Bigley V, Collin M, Manz MG, McClain K, Merad M, Allen CE. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014;211(4):669-83. Martel C, Li W, Fulp B, Platt AM, Gautier EL, Westerterp M, Bittman R, Tall AR, Chen SH, Thomas MJ, Kreisel D, Swartz MA, Sorci-Thomas MG, Randolph GJ. Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest. 2013;123(4):1571-9. Bonito AJ, Aloman C, Fiel MI, Danzl NM, Cha S, Weinstein EG, Jeong S, Choi Y, Walsh MC, Alexandropoulos K. Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J Clin Invest. 2013;123(8):3510-24 Muller TD, Lee SJ, Jastroch M, Kabra D, Stemmer K, Aichler M, Abplanalp B, Ananthakrishnan G, Bhardwaj N, Collins S, Divanovic S, Endele M, Finan B, Gao Y, Habegger KM, Hembree J, Heppner KM, Hofmann S, Holland J, Kuchler D, Kutschke M, Krishna R, Lehti M, Oelkrug R, Ottaway N, Perez-Tilve D, Raver C, Walch AK, Schriever SC, Speakman J, Tseng YH, Diaz-Meco M, Pfluger PT, Moscat J, Tschop MH. p62 links beta-adrenergic input to mitochondrial function and thermogenesis. J Clin Invest. 2013;123(1):469-78. Romberg N, Chamberlain N, Saadoun D, Gentile M, Kinnunen T, Ng YS, Virdee M, Menard L, Cantaert T, Morbach H, Rachid R, Martinez-Pomar N, Matamoros N, Geha R, Grimbacher B, Cerutti A, CunninghamRundles C, Meffre E. CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest. 2013;123(10):4283-93.

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Idoyaga J, Fiorese C, Zbytnuik L, Lubkin A, Miller J, Malissen B, Mucida D, Merad M, Steinman RM. Specialized role of migratory dendritic cells in peripheral tolerance induction. J Clin Invest. 2013;123(2):844-54. 39. Agarwal S, Cunningham-Rundles C. Treatment of hypogammaglobulinemia in adults: a scoring system to guide decisions on immunoglobulin replacement. J Allergy Clin Immunol. 2013;131(6):1699-701. 40. Berin MC, Mayer L. Can we produce true tolerance in patients with food allergy? J Allergy Clin Immunol. 2013;131(1):14-22. 41. Ford LS, Bloom KA, Nowak-Wegrzyn AH, Shreffler WG, Masilamani M, Sampson HA. Basophil reactivity, wheal size, and immunoglobulin levels distinguish degrees of cow's milk tolerance. J Allergy Clin Immunol. 2013;131(1):180-6 e1-3. 42. Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Pai SY, Ballard B, Bauer SC, Bleesing JJ, Boyle M, Brower A, Buckley RH, van der Burg M, Burroughs LM, Candotti F, Cant AJ, Chatila T, CunninghamRundles C, Dinauer MC, Dvorak CC, Filipovich AH, Fleisher TA, Bobby Gaspar H, Gungor T, Haddad E, Hovermale E, Huang F, Hurley A, Hurley M, Iyengar S, Kang EM, Logan BR, Long-Boyle JR, Malech HL, McGhee SA, Modell F, Modell V, Ochs HD, O'Reilly RJ, Parkman R, Rawlings DJ, Routes JM, Shearer WT, Small TN, Smith H, Sullivan KE, Szabolcs P, Thrasher A, Torgerson TR, Veys P, Weinberg K, Zuniga-Pflucker JC. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol. 2014;133(2):335-47. 43. Menard L, Cantaert T, Chamberlain N, Tangye SG, Riminton S, Church JA, Klion A, Cunningham-Rundles C, Nichols KE, Meffre E. Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance. J Allergy Clin Immunol. 2014;133(4):1149-61. 44. Martinez-Gallo M, Radigan L, Almejun MB, Martinez-Pomar N, Matamoros N, Cunningham-Rundles C. TACI mutations and impaired Bcell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013;131(2):468-76. 45. Shearer WT, Fleisher TA, Buckley RH, Ballas Z, Ballow M, Blaese RM, Bonilla FA, Conley ME, Cunningham-Rundles C, Filipovich AH, Fuleihan R, Gelfand EW, Hernandez-Trujillo V, Holland SM, Hong R, Lederman HM, Malech HL, Miles S, Notarangelo LD, Ochs HD, Orange JS, Puck JM, Routes JM, Stiehm ER, Sullivan K, Torgerson T, Winkelstein J. Recommendations for live viral and bacterial vaccines in

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immunodeficient patients and their close contacts. J Allergy Clin Immunol. 2014;133(4):961-6. Maglione PJ, Ko HM, Beasley MB, Strauchen JA, Cunningham-Rundles C. Tertiary lymphoid neogenesis is a component of pulmonary lymphoid hyperplasia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;133(2):535-42. Bhardwaj N, Ishmael FT. Cytokine gene expression profiling to help identify a safe antibiotic in a patient with drug rash with eosinophilia and systemic symptoms. J Allergy Clin Immunol Pract. 2013;1(5):531-3. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, Adedokun OJ, Guzzo C, Colombel JF, Reinisch W, Gibson PR, Collins J, Jarnerot G, Hibi T, Rutgeerts P. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):85-95; quiz e14-5. Rabinowitz KM, Wang Y, Chen EY, Hovhannisyan Z, Chiang D, Berin MC, Dahan S, Chaussabel D, Ma'ayan A, Mayer L. Transforming growth factor beta signaling controls activities of human intestinal CD8(+)T suppressor cells. Gastroenterology. 2013;144(3):601-12 e1. Narula N, Peyrin-Biroulet L, Colombel JF. Combination therapy with methotrexate in inflammatory bowel disease: time to COMMIT? Gastroenterology. 2014;146(3):608-11. Osterman MT, Sandborn WJ, Colombel JF, Robinson AM, Lau W, Huang B, Pollack PF, Thakkar RB, Lewis JD. Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn's disease. Gastroenterology. 2014;146(4):941-9. Hamard PJ, Barthelery N, Hogstad B, Mungamuri SK, Tonnessen CA, Carvajal LA, Senturk E, Gillespie V, Aaronson SA, Merad M, Manfredi JJ. The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo. Genes Dev. 2013;27(17):1868-85. Parrish NF, Gao F, Li H, Giorgi EE, Barbian HJ, Parrish EH, Zajic L, Iyer SS, Decker JM, Kumar A, Hora B, Berg A, Cai F, Hopper J, Denny TN, Ding H, Ochsenbauer C, Kappes JC, Galimidi RP, West AP, Jr., Bjorkman PJ, Wilen CB, Doms RW, O'Brien M, Bhardwaj N, Borrow P, Haynes BF, Muldoon M, Theiler JP, Korber B, Shaw GM, Hahn BH. Phenotypic properties of transmitted founder HIV-1. Proc Natl Acad Sci U S A. 2013;110(17):662633. Sun L, Zhu LL, Lu P, Yuen T, Li J, Ma R, Baliram R, Moonga SS, Liu P, Zallone A, New MI, Davies TF, Zaidi M. Genetic confirmation for a central role for TNFalpha in the direct action of thyroid stimulating

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hormone on the skeleton. Proc Natl Acad Sci U S A. 2013;110(24):98916. Azeloglu EU, Hardy SV, Eungdamrong NJ, Chen Y, Jayaraman G, Chuang PY, Fang W, Xiong H, Neves SR, Jain MR, Li H, Ma'ayan A, Gordon RE, He JC, Iyengar R. Interconnected network motifs control podocyte morphology and kidney function. Sci Signal. 2014;7(311):ra12. Faith JJ, Ahern PP, Ridaura VK, Cheng J, Gordon JI. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med. 2014;6(220):220ra11. Brown BD. Stealth gene therapy. Blood. 2013;121(12):2168-9. Salazar AM, Erlich RB, Mark A, Bhardwaj N, Herberman RB. Therapeutic In-Situ Autovaccination against Solid Cancers with Intratumoral PolyICLC: Case report, Hypothesis, and Clinical Trial. Cancer Immunol Res. 2014. da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I, Bhardwaj N. Reversal of NK-Cell Exhaustion in Advanced Melanoma by Tim-3 Blockade. Cancer Immunol Res. 2014;2(5):410-22. Odunsi K, Matsuzaki J, James SR, Mhawech-Fauceglia P, Tsuji T, Miller A, Zhang W, Akers SN, Griffiths EA, Miliotto A, Beck A, Batt CA, Ritter G, Lele S, Gnjatic S, Karpf AR. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res. 2014;2(1):37-49. Lavin Y, Merad M. Macrophages: gatekeepers of tissue integrity. Cancer Immunol Res. 2013;1(4):201-9. Matsuzaki J, Tsuji T, Luescher I, Old LJ, Shrikant P, Gnjatic S, Odunsi K. Nonclassical Antigen-Processing Pathways Are Required for MHC Class II-Restricted Direct Tumor Recognition by NY-ESO-1-Specific CD4+ T Cells. Cancer Immunol Res. 2014;2(4):341-50. Kitano S, Tsuji T, Liu C, Hirschhorn-Cymerman D, Kyi C, Mu Z, Allison JP, Gnjatic S, Yuan JD, Wolchok JD. Enhancement of tumor-reactive cytotoxic CD4(+) T cell responses after ipilimumab treatment in four advanced melanoma patients. Cancer Immunol Res. 2013;1(235). Tsuji T, Sabbatini P, Jungbluth AA, Ritter E, Pan L, Ritter G, Ferran L, Spriggs D, Salazar AM, Gnjatic S. Effect of Montanide and Poly-ICLC Adjuvant on Human Self/Tumor Antigen-Specific CD4+ T Cells in Phase I Overlapping Long Peptide Vaccine Trial. Cancer Immunol Res. 2013;1(5):340-50. Furtado GC, Pacer ME, Bongers G, Benezech C, He Z, Chen L, Berin MC, Kollias G, Caamano JH, Lira SA. TNFalpha-dependent development of lymphoid tissue in the absence of RORgammat(+) lymphoid tissue inducer cells. Mucosal Immunol. 2014;7(3):602-14. (cover article).

65. Roda G, Jianyu X, Park MS, Demarte L, Hovhannisyan Z, Couri R, Stanners CP, Yeretssian G, Mayer L. Characterizing CEACAM5 interaction with CD8alpha and CD1d in intestinal homeostasis. Mucosal Immunol. 2014;7(3):615-24. 66. Mathern DR, Laitman LE, Hovhannisyan Z, Dunkin D, Farsio S, Malik TJ, Roda G, Chitre A, Iuga AC, Yeretssian G, Berin MC, Dahan S. Mouse and human Notch-1 regulate mucosal immune responses. Mucosal Immunol. 2014. 67. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31:563-604. 68. Tomer Y. Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics. Annu Rev Pathol. 2014;9:147-56. 69. Puga I, Cerutti A. Protection by natural IgG: a sweet partnership with soluble lectins does the trick! EMBO J. 2013;32(22):2897-9. 70. Martin JC, Beriou G, Heslan M, Chauvin C, Utriainen L, Aumeunier A, Scott CL, Mowat A, Cerovic V, Houston SA, Leboeuf M, Hubert FX, Hemont C, Merad M, Milling S, Josien R. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol. 2014;7(1):101-13. 71. Berin MC, Wang W. Reduced severity of peanut-induced anaphylaxis in TLR9-deficient mice is associated with selective defects in humoral immunity. Mucosal Immunol. 2013;6(1):114-21. 72. O'Brien M, Manches O, Bhardwaj N. Plasmacytoid dendritic cells in HIV infection. Adv Exp Med Biol. 2013;762:71-107. 73. Mourao-Sa D, Roy S, Blander JM. Vita-PAMPs: signatures of microbial viability. Adv Exp Med Biol. 2013;785:1-8. 74. Berres ML, Allen CE, Merad M. Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases. Adv Immunol. 2013;120:127-61. 75. Kaaya SF, Blander J, Antelman G, Cyprian F, Emmons KM, Matsumoto K, Chopyak E, Levine M, Smith Fawzi MC. Randomized controlled trial evaluating the effect of an interactive group counseling intervention for HIV-positive women on prenatal depression and disclosure of HIV status. AIDS Care. 2013;25(7):854-62. 76. Bloch N, O'Brien M, Norton TD, Polsky SB, Bhardwaj N, Landau NR. HIV type 1 infection of plasmacytoid and myeloid dendritic cells is restricted by high levels of SAMHD1 and cannot be counteracted by Vpx. AIDS Res Hum Retroviruses. 2014;30(2):195-203.

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fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-kappaB signaling. Oncogene. 2014;33(19):252030. Wang Q, Chikina MD, Pincas H, Sealfon SC. Homer1 alternative splicing is regulated by gonadotropin-releasing hormone and modulates gonadotropin gene expression. Mol Cell Biol. 2014;34(10):1747-56. Pincas H, Choi SG, Wang Q, Jia J, Turgeon JL, Sealfon SC. Outside the box signaling: secreted factors modulate GnRH receptor-mediated gonadotropin regulation. Mol Cell Endocrinol. 2014;385(1-2):56-61. Wang Q, Chikina M, Zaslavsky E, Pincas H, Sealfon SC. beta-catenin regulates GnRH-induced FSHbeta gene expression. Mol Endocrinol. 2013;27(2):224-37. Pan PY, Chen HM, Chen SH. Myeloid-derived suppressor cells as a Trojan horse: A cellular vehicle for the delivery of oncolytic viruses. Oncoimmunology. 2013;2(8):e25083. Moreno JL, Holloway T, Rayannavar V, Sealfon SC, Gonzalez-Maeso J. Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice. Neurosci Lett. 2013;536:69-73. Moreno JL, Holloway T, Umali A, Rayannavar V, Sealfon SC, GonzalezMaeso J. Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice. Psychopharmacology (Berl). 2013;225(1):217-26. Chu A, Genden E, Posner M, Sikora A. A patient-centered approach to counseling patients with head and neck cancer undergoing human papillomavirus testing: a clinician's guide. Oncologist. 2013;18(2):180-9. Postow MA, Luke JJ, Bluth MJ, Ramaiya N, Panageas KS, Lawrence DP, Ibrahim N, Flaherty KT, Sullivan RJ, Ott PA, Callahan MK, Harding JJ, D'Angelo SP, Dickson MA, Schwartz GK, Chapman PB, Gnjatic S, Wolchok JD, Hodi FS, Carvajal RD. Ipilimumab for patients with advanced mucosal melanoma. Oncologist. 2013;18(6):726-32. Bradley J, Jiang N, Levy L, Richards-Kortum R, Sikora A, Smouha E. Highresolution microendoscope images of middle ear cholesteatoma and surrounding tissue: evaluation of interobserver concordance. Otolaryngol Head Neck Surg. 2014;150(4):654-8. Caubet JC, Masilamani M, Rivers NA, Mayer L, Sampson HA. Potential non-T cells source of interleukin-4 in food allergy. Pediatr Allergy Immunol. 2014;25(3):243-9. Grumolato L, Liu G, Haremaki T, Mungamuri SK, Mong P, Akiri G, LopezBergami P, Arita A, Anouar Y, Mlodzik M, Ronai ZA, Brody J, Weinstein DC, Aaronson SA. beta-Catenin-independent activation of TCF1/LEF1 in

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Appendix II

Fundamentals in Immunology Schedule

66

APENDIX II Fundamentals in Immunology Schedule Course 1501 Fall 2013 Week 1 1 1 1

Lecture Title 1 Overview of the Immune system Innate Immunity 2 Complement I 3 Complement II

Day, Date Monday 9/9/2013

Room 5-210C

Time 9-10AM

Lecturer Alexandropoulos

Tuesday 9/10/2013 Wednesday 9/11/2013

5-210C 5-210C

9-10AM 9-10AM

Heeger Heeger

1 1

4 5

Pattern Recognition Receptors I Innate Immunity I/Cell components

Thursday 9/12/2013 Friday 9/13/2013

5-210C 5-210C

9-10AM 9-10AM

Yeretsian Merad

Week 2

6

Monday 9/16/2013

5-210C

9-10AM

Merad

2 2

7

Tuesday 9/17/2013 Wednesday 9/18/2013

Moran

8 9

Thursday 9/19/2013 Friday 9/20/2013

5-210C 5-210C 5-210C 5-210C 5-210C 5-210C

9-10AM 9-10AM

2 2

Innate Immunity II/Dentritic cells and Macrophages Innate Response to Infection Quiz I Antigen Recognition/Presentation B and T cells Antigen Recognition by B cells VDJ Recombination B/T cells

9-10AM 9-10AM

Cortes Cortes

Week 3 3 3 3 3

10 11 12 13 14

Antibody repertoire diversification Antigen recognition by T cells Antigen presentation to T cells Antigen Receptor Signaling B cell Development

Monday 9/23/2013 Tuesday 9/24/2013 Wednesday 9/25/2013 Thursday 9/26/2013 Friday 9/27/2013

5-210C 5-210C 5-210C 5-210C 5-210C

9-10AM 9-10AM 9-10AM 9-10AM 9-10AM

Cortes Ting Ting Alexandropoulos Cortes

Week 4 4

15 16

T cell development I T cell development II

Monday 9/30/2013 Tuesday 10/1/2013

5-210C 5-210C

9-10AM 9-10AM

Alexandropoulos Alexandropoulos

67

APCs and T cell-mediated Immunity APCs /T cell priming T cell Differentiation Humoral Immunity

Wednesday 10/2/2013 Thursday 10/3/2013 Friday 10/4/2013

5-210C 5-210C 5-210C

9-10AM 9-10AM 9-10AM

Esplugues Esplugues Cerutti

4 4 4

17 18 19

Week 5 5 5 5 5

20 21

Immune Response to infection Immunological Memory review review Mid Term Exam

Monday 10/7/2013 Tuesday 10/8/2012 Wednesday 10/9/2013 Thursday 10/10/2013 Friday 10/11/2013

5-210C 5-210C 5-210C 5-210C 5-210C

9-10AM 9-10AM 9-10AM 9-10AM 9-12noon

Ting Espluges TAs TAs

Week 6

22 23

Monday 10/14/2013 Tuesday 10/15/2013

Lira Lira

24 25 26

5-210C 5-210C 5-210C 5-210C 5-210C

9-10AM 9-10AM

6 6 6

Effector cell Trafficking II Homeostatic, Imm. cell traffic. I Immune System in health and Disease Mucosal Immunity I (Immune cells) Mucosal Immunity III (epithelium) Mucosal Immunity II pathogen/ host interactions

5-210C

9-10AM 9-10AM 9-10AM

Yeretsian Dahan Yeretsian

6

Wednesday 10/16/2013 Thursday 10/17/2013 Friday 10/18/2013

Week 7 7

27 28

Microbiota I Microbiota II

Monday 10/21/2013 Tuesday 10/22/13

5-210C 5-210C

9-10AM 9-10AM

7

29

Immune-Deficiencies I

Wednesday 10/23/2013

5-210C

9-10AM

7 7

30 31

Immune-Deficiencies II Aquired Immune Deficiency Syndrome

Thursday 10/24/2013 Friday 10/25/2013

5-210C 5-210C

9-10AM 9-10AM

Faith Clemente CunninghamRundles CunninghamRundles Ben Chen

Week 8 8

32

Quiz II Allergy and hypersensitivity

Monday 10/28/2013 Tuesday 10/29/2013

5-210C

9-10AM

Berin

68

8 8 8

33 34 35

Mechanisms of autoimmunity Autoimmunity and transplantation Tumor Immunology II

Wednesday 10/30/13 Thursday 10/31/2013 Friday 11/1/2013

5-210C 5-210C 5-210C

9-10AM 9-10AM 9-10AM

Alexandropoulos Heeger Shu-Hsia Chen

Week 9 9 9 9 9

36 37

Tumor Immunology I Vaccines I review review Final Exam

Monday 11/4/2013 Tuesday 11/5/2013 Wednesday 11/6/2013 Thursday 11/7/2013 Friday 11/8/2013

5-210C 5-210C

9-10AM 9-10AM 9-10AM 9-10AM 9-12noon

Sikora Gnjatic TAs TAs

69

5-210C 5-210C

70

Appendix III Immunology Seminar Series

APPENDIX III Immunology Institute Seminar Series 2009

2007 March 20 May 1 June 26 September 14 October 23 November 9 December 14

Ralph Steinman Dan Littman Peter Heeger Juan Lafaille Andrea Cerutti Phil Murphy Warren Strober

2008 January 11 February 8 March 14 April 11 May 9 June 13 July 11 August 8 September 12 October 10 November 14 December 12

71

Eric Pamer Andy Luster Richard Ransohoff Brian Kelsall Ronald Germain Michael Brenner Richard Flavell Yong-Jun Liu Nancy Ruddle Abbul Abbas Jeffrey Bluestone Luigi Notarangelo

January 20 February 10 March 10 April 14 May 12 June 9 July 14 August 11 September 8 October 13 November 10 December 1

Kevin Tracey Ruslan Medzhitov Marc Jenkins Casey Weaver Betty Diamond Ulrich von Andrian Michael Sixt Gabriel Nuñez Leo Lefrancois Yasmine Belkaid Alan Sher Stefan Feske

2010 January 12 February 9 March 9 April 13 May 11 June 8 July 13 August 10 September 14 October 12

Ira Mellman Jane Salmon Charles Elson Alexander Rudensky Adolfo García-Sastre Gérard Eberl, Marco Colonna Sarkis Mazmanian Chen Dong Douglas Green

November 9 December 14

Lisa Coussens Mark Anderson

December 11

Caetano Reis e Sousa Alessandra Pernis R. Balfour Sartor Robert Coffman Jeffrey William Pollard Donna Farber Douglas Green Christopher Hunter Virginia Pascual Jo Viney Andrea Cerutti Drew Pardoll

February 12 March 12 April 2 May 14 June 11 July 9 August 13 September 10 November 12 December 10

Michael Overholtzer

2013

2011 January 11 February 8 March 8 April 12 May 10 June 14 July 12 August 9 September 13 October 11 November 8 December 13 2012 February 14 March 6 March 13 April 10 May 8 June 12 July 10 August 14 September 13 October 9 November 13

72

Benjamin Segal Catharina Svanborg Michael Dustin Dan Littman Giorgio Trinchieri Jayanta Chaudhuri Steven Ziegler Juan Lafaille Paul Frenette Paul Kubes Akiko Iwaski

Sankar Ghosh Richard Blumberg Valerie Verhasselt Christian Jobin Thorsten Mempel Andrew Bowie TJ Chen Jonathan Kagan Jose Clemente Johanna Joyce

2014 January 14 February 11 March 11 April 8 May 13 June 10 July 8 August 12 September 9 October 14 November 11 December 9

Ramnik Xavier Laurence Turka Judy Cho Nina Papavasiliou Warren Pear Mitchell Kronenberg Wendy Garrett Emma Guttman Gregory Sonnenberg George Kollias Chyi-Song Hsieh Kate Fitzgerald

73

Appendix IV Immunotherapy trials

APPENDIX IV Immunotherapy Studies Study Title Immune Modulators: NY-ESO-1 Vaccine in combination with Imiquimod NY-ESO-1 Vaccine in combination with Resiquimod and Montanide NY-ESO-1 Vaccine in combination with PolyICLC and Montanide NY-ESO-1 long peptide in combination with Poly-ICLC and Montanide In Situ Vaccine for Low-Grade Lymphoma: Combination of Intratumoral Flt3L and PolyICLC With Low-Dose Radiotherapy Treatment of Solid Tumors With Intratumoral Hiltonol® (Poly-ICLC) NY-ESO-1 protein-DEC-205 vaccine with PolyICLC and Flt3L Dendritic Cell Vaccine: DC with NY-ESO-1 and Melan-A/MART-1 long peptide and Poly-ICLC

Disease

PI/funding

Status

Melanoma

Nina Bhardwaj Cancer Research Institute Nina Bhardwaj Cancer Research Institute Nina Bhardwaj Cancer Research Institute Sacha Gnjatic Cancer Research Institute Joshua Brody NIH, Damon Runyon

Completed

Solid Cancers

Nina Bhardwaj

Recruiting Patients

Melanoma

Nina Bhardwaj (CITN/NCI)

Planning

Melanoma

IND obtained

Host DC Vaccine post allo HCT

Lymphoma, multiple myeloma, and chronic lymphocytic leukemia Kidney

Nina Bhardwaj Melanoma Research Foundation Keren Osman NIH

Michael Palese (Argos Therapeutics)

Recruiting Patients

Autologous Dendritic Cell Treatment in Advanced Renal Cell Carcinoma

74

Melanoma Melanoma Ovarian Cancer Lymphoma

Completed Completed Completed Recruiting Patients

Recruiting Patients

PET/MR Assessment of Sipuleucel T Treatment for Metastatic Castration Resistant Prostate Cancer

Prostate Cancer

Co-I: Nina Bhardwaj (Dendreon)

Recruiting Patients

Sipuleucel T in patients previously treated with Sipuleucel T

Prostate Cancer

Simon Hall (Dendreon)

Recruiting Patients

Active Immunotherapy using Dendritic cellBased treatment for Late stage Prostate cancer Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer Checkpoint Blockade Inhibitors: Ipilimumab and Cytoxan

Prostate Cancer

Willilam Oh (Sotio)

Planning

Glioblastoma multiforme

Adilia Hormigo (Northwest Biotherapeutics)

Planning

Melanoma

Nina Bhardwaj (BMS)

Completed

Gemcitabine, Cisplatin plus Ipilimumab

Urinary Bladdder

Matthew Galsky (BMS)

Recruiting Patients

NY-ESO-1 Vaccine in Combination With Ipilimumab in Patients With Unresectable or Metastatic Melanoma

Melanoma

Philip Friedlander Recruiting Patients Cancer Vaccine Collaborative (CVC)

Safety and Efficacy of Talimogene Laherparepvec and Ipilimumab

Melanoma

Yvonne Saenger Amgen

Recruiting Patients

NY-ESO-1 protein vaccine with Poly-ICLC and checkpoint blockade

Melanoma

Friedlander/Posner/ Saenger/ Bhardwaj (CVC)

Planning

Multiple Myeloma

Hearn Cho Cancer Research Institute

Completed enrollment

POL-103A Polyvalent Melanoma Vaccine

Melanoma

Yvonne Saenger (Polynoma)

Recruiting Patients

Pathway Inhibitors: The Effects of Treatment With Vemurafenib on

Melanoma

Philip Friedlander

Recruiting Patients

Adoptive Cell Therapies: MAGE-A3 Protein + AS15 as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

75

the Immune System in Advanced Melanoma

Genentech

Safety and Efficacy Study of Idelalisib (GS-1101, CAL-101) in Patients With Previously Treated Low-grade Lymphoma

Lymphoma

Joshua Brody

Recruiting Patients

Ibrutinib (BTK inhibitor) in combination with Carfilzomib

Multiple Myeloma

Ajai Chari

Recruiting Patients

Ibrutinib in Multiple Myeloma

Multiple Myeloma

Sundar Jagannath

Recruiting Patients

Proteasome Inhibitors: Safety and Activity of ONYX 0912

Multiple Myeloma

Recruiting Patients

Pharmacokinetics study of MLN9708

Multiple Myeloma

Sundar Jagannath (Onyx Pharmaceuticals) Ajai Chari (Takeda)

Squamous Cell Carcinoma Solid Cancers

Andrew Sikora (Advaxis)

Recruiting Patients

Peter Palese

Planning

Pancreatic Cancer

Max Sung (Aduro Biotech)

Planning

HIV

Recruiting patients

HIV

Nina Bhardwaj NIH, Campbell Foundation Nina Bhardwaj

Supporting In negotiation with CTI-Pfizer for funding /collaboration

Comments 33 mAb generated that specifically bind DQ8-insulin peptide complex as

Status Testing blockade of T cell activation in vitro and in vivo

Bacterial and Viral Vectors: Vaccination with Neoadjuvant ADXS11-001 Newcastle Disease Oncolytic Virus in Solid Cancers Efficacy of Combination Listeria/GVAX Immunotherapy in the Pancreatic Cancer Setting HIV Infection: Poly-ICLC in Treated HIV Infection AT-2 HIV DC in Treated HIV Infection Monoclonal antibodies: Investigator Project description Tomer mAb that block DQ8-insulin peptide T cell activation.

76

Recruiting Patients

Planning

S. Chen

Agonistic and/or antagonistic NIH funded project. mAb against the LILRB family Also, in negotiation of immune regulators with CTI, Accelerate.

B. Chen

Human mAb capable of neutralizing HIV cell to cell spread from HIV non progressors

Basler

Human mAb capable of neutralizing alphaviruses (VEEV) from convalescent patient blood.

Sampson

Generation of capture ELISA for measurements of PAFAcytyl hydrolase as potential biomarker for anaphylactic susceptibility Generation of mAb specific for HPV positive head and neck cancers

Sikora

CunninghamRundles

77

mAb specific for TACI short version

NIH funding obtained for this project NIHR21 Identifying Human Antibodies That Potently Neutralize Cell-To-Cell HIV Infection NIH-R21 1R21AI101794-01A1 Naturally occurring human antibodies to alphavirus infection Institutional funding source.

measured by flow cytometry 75 mAb with specificity for LILRB members produced that bind to receptors on cell surface More than 50 mAb with specificity for virus have been generated from human blood.

Bait being produced to sort cells from subject samples

80 mAb produced, affinity measured, binned by specificity using Octet analysis and ELISA generated and validated. Institutional “Request Panel of 50 monoclonal for Target” initiated antibodies produced and project. NIH funding tested. Many show applications specificity for HPV tumors submitted. including those derived from cervical tissue. NIH funded project Using unique vesicle immunization strategy mAb with specificity for TACI short were produced

Agonist and antagonists testing of mAb underway. Both types identified in preliminary assays Neutralization assays are underway with some positives identified.

Development phase

Luminex style assay is in development.

Testing for function of antibodies on panels of HPV tumor cells. Lead candidate identification underway. Testing of mAb function underway. Additional mAb are in development

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Appendix V Biosketches

APPENDIX III BIOSKETCHES BIOGRAPHICAL SKETCH NAME Alexandropoulos, Konstantina EDUCATION/TRAINING INSTITUTION AND LOCATION Mercy College, Dobbs Ferry, New York Hunter College, City University of New York A. Personal Statement Dr. Alexandropoulos has been an investigator at the Mount Sinai School of Medicine since July 2008 when she was appointed as an Associate Professor. Over the past several years the Dr. Alexandropoulos’ research has focused on elucidating signaling mechanisms that regulate the function of T lymphocytes. Recently her research focus has been on thymic epithelial cell development and how mutations that affect the function of these cells regulate T cell development and function. The PI has accumulated expertise with purifying, staining and analyzing thymic epithelial cell populations, T cells from many tissues, immunohistochemical assays, assaying for autoimmune manifestations, T cell-mediated immune responses and studying signaling pathways in these cells. This expertise is relevant and will be applied towards the experiments described in this application. B. Positions and Honors Positions:

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POSITION TITLE Associate Professor DEGREE B.S. Ph.D.

YEAR(s) 1986 1992

FIELD OF STUDY Biology Molecular Biology

1984-86: Research Assistant (during undergraduate studies), laboratory of Dr. Lola Margolis, New York Medical College, Valhalla, New York 1987-92: Graduate student, laboratory of Dr. David Foster, Hunter College, City University of New York 1992-97: Postdoctoral fellow in the laboratory of Dr. David Baltimore, Rockefeller University, New York (1992-94) and Massachusetts Institute of Technology, Cambridge, Massachusetts (1994-97) 1997-6/08: Assistant Professor, Department of Pharmacology, College of Physicians & Surgeons, New York 7/08-present Associate Professor, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine Honors: B.S., Magna cum laude; M.S./Ph.D., Magna cum laude Scholarship and Welfare Fund of the Alumni Association of Hunter College The Frederick Velergakis Graduate Award

NIH/NCI Postdoctoral Fellowship, 1993-96 Anna Fuller Fund Fellowship in Molecular Oncology, 1996-97 Elected member of the Henry Kunkel Society, 2013 C. Selected Peer-reviewed Publications 1. Qureshi SA, Alexandropoulos K, Joseph CK, Spangler R, and Foster DA. (1991) Cholera toxin induces expression of the immediate-early response gene JE via a cyclic AMPindependent signaling pathway. Mol Cell Biol 11:102-107. 2. Alexandropoulos K, Joseph CK, Spangler R, and Foster DA. (1991) Evidence that a G-protein transduces signals initiated by the protein-tyrosine-kinase v-Fps. J Biol Chem 266:1558315586. 3. Alexandropoulos K, Qureshi SA, Sukhatme VP, and Foster DA. (1992) v-Fps-induced expression of Egr-1 is independent of protein kinase C and dependent upon clustered serum response elements. Nucleic Acid Res 20:2355-2359. 4. Qureshi SA, Rim M, Alexandropoulos K, Berg K, Sukhatme VP, and Foster DA. (1992) Sustained induction of Egr-1 by vSrc correlates with a lack of fos-mediated repression of the Egr-1 promoter. Oncogene 7:121-125. 5. Qureshi SA, Alexandropoulos K, Rim M, Joseph CK, Bruder JM, Rapp UR, and Foster DA. (1992) Evidence that Ras mediates two distinguishable intracellular signals activated by v-Src. J Biol Chem 267:17635-17639. 6. Alexandropoulos K, Qureshi SA, and Foster DA. (1992) HaRas functions downstream from protein kinase C in v-Fpsinduced gene expression mediated by TPA response elements. Oncogene 8:803-807. 7. Alexandropoulos K, Qureshi SA, Bruder JT, Rapp U, and Foster DA. (1992) The induction of Egr-1expression by v-Fps is via a PKC-independent pathway that is sequentially dependent upon HaRas and Raf-1.Cell Growth and Diff 3:731737.

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8. Jiang H, Alexandropoulos K, Song J, and Foster DA. (1994) Evidence that v-Src-induced phospholipase D activity is mediated by a G-protein. Mol Cell Biol 14:3676-3682. 9. Baltimore, D., Ren, R., Cheng, G., Alexandropoulos, K., and Cicchetti, P. (1995). A nuclear tyrosine kinase becomes a cytoplasmic oncogene. Ann. NY Acad. Sci. 758: 339-344. 10. Alexandropoulos K, Cheng G, Baltimore D. (1995) Novel proline-rich sequences bind to SH3 domains with individual specificities. Proc Natl Acad Sci. USA 92:3110-3114. 11. Alexandropoulos K and Baltimore D. (1996) Coordinate activation of c-Src by SH3 and SH2 binding sites on a novel p130Cas-related protein, Sin. Genes and Dev 10:1341-1355. 12. Xing, L., Ge, C., Zeltser, R., Maskevitch, G.R., Mayer, B.J., and Alexandropoulos, K. 2000. c-Src signaling induced by the adapters Sin and Cas is mediated by the Rap1 GTPase. Mol. Cell. Biol. 20:7363-7377. 13. Yang, L.T., Alexandropoulos, K., and Sap J. 2002. Expression of protein tyrosine phosphatase alpha and the adaptor Crk, and is independent of sustained ERK activation. J. Biol. Chem. 277:17406. 14. Donlin, L.T., Roman, C.A., Adlam, M., Regelmann, A.G., and Alexandropoulos, K. 2002. Defective thymocyte maturation by transgenic expression of a truncated form of the lymphocyte adapter molecule and Fyn substrate, Sin. J. Immunol. 169:6900-6909. 15. Alexandropoulos, K., Donlin, L.T., Xing, L. and Regelmann, A.G. 2003. Sin: Good or Bad? A T lymphocyte perspective. Immonol. Rev. 192: 181-195. 16. Xing, L., Donlin, L.T., Miller, R.H., and Alexandropoulos, K. 2004. The Adapter Molecule Sin Regulates T-Cell-ReceptorMediated Signal Transduction by Modulating Signaling Substrate Availability. Mol. Cell. Biol. 24: 4581-4592.

17. Donlin, L.T., Danzl, N., Wanjalla, C., and Alexandropoulos, K. 2005. Deficiency in Expression of the Signaling Protein Sin/Efs Leads to T lymphocyte Activation and Mucosal Inflammation Mol. Cell. Biol. 2005. 25:11035-11046. 18. Natarajan, M., Stewart Jr., J.E., Golemis, E., Pugacheva, E., Alexandropoulos, K., Grammer, J.R., and Gladson, C.L. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene, 2006. 25:1721-1732. 19. Regelmann, A.G., Danzl, N.M., Wanjalla C., and Alexandropoulos, K. Chat-H regulates T lymphocyte trafficking by acting upstream of Rap1 in chemokine-induced inside-out signaling. Immunity, 2006. 25:907-918. 20. Alexandropoulos, K. and Regelmann, A.G. Chat-H/CasL: A novel adapter complex that regulates T lymphocyte physiology. Invited review. Imm. Rev. 2009. 232(1):160-74. 21. Danzl, N.M., Donlin, L.T., and Alexandropoulos, K. Regulation of Medullary Thymic Epithelial Cell Differentiation and Function by the Signaling Protein Sin. J. Exp. Med. 2010. 207(5):999-1013. 22. Alexandropoulos, K., Danzl, N.M. Medullary thymic epithelial cells: Antigen presenting cells regulating T cell selection and function. 2012. Immunol. Res. 54 (1-3): 177-190. 23. Bonito, A.J., Aloman, C., Fiel, M.I., Danzl, N.M., Cha, S., Weinstein, E.G., Jeong, S., Choi, Y., Walsh, M.C., and Alexandropoulos, K. Medullary thymic epithelial cell depletion results in Autoimmune Hepatitis. J. Clin. Inv. 2013. 123(8): 3510-3524. 24. Danzl, N.M., Jeong, S., Choi, Y., and Alexandropoulos, K. Identification of novel thymic epithelial cell subsets whose differentiation is regulated by RANKL and Traf6. PLoS ONE. 2014. 9(1): c86129.

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25. Riccomagno, M.M., Sun, L.O., Brady, C.M., Alexandropoulos, K., Seo, S., Kurokawa, M., Kolodkin, A.L. Cas adaptor proteins organize the retinal ganglion cell layer downstream of integrin signaling. Neuron. 2014 81(4):779-86.

BIOGRAPHICAL SKETCH NAME Berin, M. Cecilia EDUCATION/TRAINING INSTITUTION AND LOCATION Queen’s University, Kingston, Canada Queen’s University, Kingston, Canada McMaster University, Hamilton, Canada University of California, San Diego, La Jolla, California A. Personal Statement My laboratory studies immune mechanisms of tolerance and allergic sensitization to foods, with an emphasis on mucosal immunology. We have identified mechanisms by which gastrointestinal dendritic cells, epithelial cells, and T cells communicate with each other contributing to intestinal homeostasis and food allergy. Within the Consortium of Food Allergy Research (CoFAR, PI Hugh Sampson), my lab is studying the immune basis of tolerance to foods in response to immunotherapy in human subjects. B. Positions and Honors Academic Positions 11/2001 – 01/2005 Instructor, Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 01/2005 – 01/2012 Assistant Professor, Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 01/2012-present Associate Professor, Department of Pediatrics, Mount Sinai School of Medicine, New York, NY Honors/Awards 1999-2002 Canadian Institute of Health Research Postdoctoral Fellowship Professional Activities 82

POSITION TITLE Associate Professor DEGREE B.Sc.(Hons) M.Sc. Ph.D. Postdoctoral

YEAR(s) 1988-1992 1992-1994 1994-1999 1999-2001

FIELD OF STUDY Life Science Physiology Medical Sciences Mucosal Immunology

Editorial Board. American Journal of Physiology, (Gastrointestinal and Liver Physiology). 2002-2009. • International Scientific Committee, Society for Mucosal Immunology (2008-current) • Programming Committee (Experimental Biology), Gastrointestinal and Liver Section, American Physiological Society. (2008-2012) • Journal review (ad hoc): Allergy; American Journal of Physiology, Clinical and Experimental Allergy, Gastroenterology, Gut, Inflammatory Bowel Diseases, International Archives of Allergy and Immunology, Journal of Allergy and Clinical Immunology, Journal of Immunology, Journal of Leukocyte Biology, Mucosal Immunology • Grant review (ad hoc): American Institute of Biological Sciences; Chief Scientist Office (Scotland); DigestScience (France); Environmental Protection Agency (USA); Health Canada; Medical Research Council (UK), Netherlands Organisation for Scientific Research C. Selected Publications Selected Original Research Publications (12 of 39) •

1. Blazquez AB, Berin MC. Gastrointestinal Dendritic Cells induce Th2 skewing via OX40L. J Immunol,180:4441-50, 2008. 2. Blázquez AB, Knight AK, Getachew H, Bromberg JS, Lira SA, Mayer L, Berin MC. A functional role for CCR6 on proallergic T cells in the gastrointestinal tract. Gastroenterology. 138:275-84.e1-4. 2010 3. Blázquez AB, Mayer L, Berin MC. Thymic Stromal Lymphopoietin is required for gastrointestinal allergy but not oral tolerance. Gastroenterology, 139: 1301-9. 2010 4. Martos G, Lopez-Exposito I, Benchartiwong R, Berin MC, Nowak-Wegrzyn A. Mechanisms underlying differential food-allergic response to heated egg. J Allergy Clin Immunol, 127(4): 990-997.e2, 2011. 5. Nácher M, Blázquez AB, Shao B, Matesanz A, Prophete C, Berin MC, Frenette PS, Hidalgo A. Physiological Contribution of CD44 as a Ligand for E-Selectin during Inflammatory T-Cell Recruitment. Am J Pathol. 178: 2437-46, 2011. 6. Dunkin D, Berin MC, Mayer L. Allergic Sensitization to Antigens Can Be Induced via Multiple Physiologic Routes in an Adjuvant-Dependent Manner, J Allergy Clin Immunol, 128: 1251-1258.e2, 2011. 7. Leonard SA, Martos G, Wang W, Nowak-Wegrzyn A, Berin MC. Oral immunotherapy induces local protective mechanisms in the gastrointestinal mucosa. J Allergy Clin Immunol 2012;129:1579-1587 e1. 8. Berin MC, Wang W. Reduced severity of peanut-induced anaphylaxis in TLR9-deficient mice is associated with selective defects in humoral immunity. Mucosal Immunol 2013; 6:114-21. 9. Rabinowitz KM, Wang Y, Chen E, Hovhannisyan Z, Chiang D, Berin MC, et al. Transforming Growth Factor-b Signaling

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Controls Activities of Human Intestinal CD8+ T Suppressor Cells. Gastroenterology 2012. 10. Shan M, Gentile M, Yeiser JR, Walland AC, Bornstein VU, Chen K, He B, Cassis L, Bigas A, Cols M, Comerma L, Huang B, Blander JM, Xiong H, Mayer L, Berin C, Augenlicht LH, Velcich A, Cerutti A. Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals. Science. 2013 Sep 26. [Epub ahead of print] 11. Järvinen KM, Westfall JE, Seppo MS, James AK, Tsuang AJ, Feustel PJ, Sampson HA, Berin C. Role of maternal elimination diets and human milk IgA in development of cow's milk allergy in the infants. Clin Exp Allergy. 2013 Oct 28. doi: 10.1111/cea.12228. [Epub ahead of print] PubMed PMID: 24164317. 12. Mathern DR, Laitman LE, Hovhannisyan Z, Dunkin D, Farsio S, Malik TJ, Roda G, Chitre A, Iuga AC, Yeretssian G, Berin MC, Dahan S. Mouse and human Notch-1 regulate mucosal immune responses. Mucosal Immunol. 2014 Jan 15. doi: 10.1038/mi.2013.118. [Epub ahead of print] PubMed PMID: 24424521. Invited Reviews (3 of 14) 13. Berin MC and Mayer L. Can we produce true tolerance in patients with food allergy? J Allergy Clin Immunol 2013; 131:14-22. 14. Berin MC and Sampson HA. Mucosal immunology of food allergy. Current Biology 2013, 23(9):R389-400. 15. Berin MC and Sampson HA. Food allergy: an enigmatic epidemic. Trends in Immunology 2013, doi:pii: S14714906(13)00057-4 (ePub ahead of print).

BIOGRAPHICAL SKETCH NAME Bhardwaj, Nina

EDUCATION/TRAINING INSTITUTION AND LOCATION Wellesley College, MA New York University School of Medicine New York University School of Medicine New York University School of Medicine A. Personal Statement Dr. Bhardwaj is the Director of Immunotherapy and the Medical Director of the Vaccine and Cell Therapy Core facility. She is an expert on human dendritic cell (DC) subsets, specifically with respect to their isolation, biology, function and use as vaccine adjuvants in humans. She has been principal investigator for the design and implementation of several clinical trials studying novel experimental immunotherapies for melanoma and other cancers using TLR agonists or dendritic cells as adjuvants. Her lab also investigates DC biology in the tumor microenvironment as it relates to anti-melanoma immunity. B. Positions 1981 - 1982 Internship; Internal Medicine, Brigham and Womens Hospital, Boston, MA 1982 – 1984 Residency; Internal Medicine, Brigham and Womens Hospital 1986 - 1989 Post-doctoral Associate, Laboratory of Cellular Physiology & Immunology, Rockefeller University, New York, NY 1989 - 1998 Research Assistant Professor (non-tenure track), Rockefeller University 84

POSITION TITLE Professor of Medicine, Division of Hematology and Medical Oncology Director, Immunotherapy Program DEGREE B.A. M.S. M.D. Ph.D.

YEAR(s) 1975 1980 1981 1982

FIELD OF STUDY Biol.Sci. Microbiology Medicine Microbiology

1998 - 2003 Associate Professor of Clinical Investigation, Rockefeller University 1984 - 1986 Rheumatology Fellowship, Hospital for Special Surgery, New York, NY (voluntary faculty) 1987 - 2003 Assistant Attending, Department of Rheumatology, Hospital for Special Surgery, (vol. faculty) 1987 - 1990 Instructor in Medicine, Weil/Cornell Medical College, New York, NY (vol. faculty) 1990 - 1996 Assistant Professor, Department of Medicine, Weil/Cornell Medical College (vol. faculty) 1996 - 2002 Associate Professor, Department of Medicine, Weil/Cornell Medical College (vol. faculty) 2001 - 2005 Consultant in Medicine, Massachusetts General Hospital, Boston, MA (vol. faculty) 2001 - 2005 Lecturer, Harvard Medical School, Boston, MA (vol. faculty) 2008 - 2011 Co-Director, Medical Scientist Training Program, New York University School of Medicine 2002 - 2013 Professor of Medicine, Pathology, Dermatology (tenured) New York University School of Medicine, New York, NY

2002 - 2013 Director, Tumor Vaccine Program, New York University School of Medicine 2013 - present Director, Immunotherapy; Icahn School of Medicine at Mt Sinai 2013 - present Professor of Medicine, Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai 2013 - present Ward Coleman Chair in Cancer Research, Icahn School of Medicine at Mount Sinai Honors 1999 - 2008 American Society of Clinical Investigation, 1999 - 2003 NIH Study Section Member: AIDS and Related Research 2 1999 - 2004 Burroughs Welcome Clinical Scientist Award 2001 - 2006 Elizabeth Glaser Scientist Award 2002 - 2007 Doris Duke Distinguished Clinical Scientist Award 2002 - 2005 Council Treasurer, American Society for Clinical Investigation 2004 Merit Award, NIH AI44628, 2004 Scientific American Top 50 Researchers Award, (Medical Research) 2004 - 2007 Associate Editor, Journal of Clinical Investigation 2007 - present Consulting Editor, Journal of Clinical Investigation 2009 - present Association of American Physicians 2012 The Solomon A. Berson Alumni Achievement Award in Basic Science 2013 - 2014 AACR, Chair-elect Cancer Immunology Steering Committee 2013 - present Consulting editor, Cancer Immunology Research 2013 Ward Coleman Chair in Cancer Research

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C. Selected peer-reviewed publications (in chronological order out of 162) 1. Dhodapkar, M.D., Steinman, R.M., Sapp, M., Desai, H., Fossella, C., Krasovsky, J., Dohahoe, S., Dunbar, P.R., Cerundolo, V., Nixon, D.F., and Bhardwaj N. Rapid generation of broad T cell immunity in humans following a single injection of mature dendritic cells. J. Clin. Invest. 104:173-180, 1999. 2. Valmori D, Souleimanian NE, Tosello V, Bhardwaj N, Adams S, O'Neill D, Pavlick A, Escalon JB, Cruz CM, Angiulli A, Angiulli F, Mears G, Vogel SM, Pan L, Jungbluth AA, Hoffmann EW, Venhaus R, Ritter G, Old LJ, Ayyoub M. Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. PNAS. 104(21):8947-52, 2007. 3. Velazquez E.F., Jungbluth A.A., Yancovitz, M., Gnjatic, S., Adams, S., O'Neill, D.W., Zavilevich, K., Albukh, T., Christos, P., Mazumdar, M., Pavlick, A., Polsky, D., Shapiro, R., Berman, R., Spira, J., Busam, K., Osman, I., Bhardwaj N. Expression of the Cancer Testis (CT) Antigen NY-ESO-1 in Primary and Metastatic Malignant Melanoma Correlation with Serology and Prognostic Factors. Cancer Immun. 7:11, 2007. 4. Adams, S., Lowes, M., O’Neill, D.W., Schachterle, S., Romero, P., Bhardwaj N. Lack of Functionally Active MelanA26–35-Specific T Cells in the Blood of HLA-A2 Vitiligo Patients. J. Invest Derm.128(8):1977-80, 2008. 5. Adams, S., O’Neill, D., Nonaka, D., Hardin, E., Chiriboga. L., Siu, K., Cruz, C., Anguilli, A., Anguilli, F., Ritter, E., Shapiro, R., Berman, R., Berner, N., Shao, Y., Manches, O., Pan, L., Hoffman, E., Gnjatic, S., Old, L., Pavlick, A., Bhardwaj N. Vaccination for malignant melanoma using recombinant

NY-ESO-1 protein and Toll-like receptor 7 agonist imiquimod as vaccine adjuvant. J. Immunol. 181: 776-784, 2008. 6. Minkis, K., Kavanagh, D.G., Alter, G., Bogunovic, D., O'Neill, D., Adams, S., Pavlick, A., Walker, B.D., Brockman, M.A., Gandhi, R. and Bhardwaj, N. Type 2 Bias of T Cells Expanded from the Blood of Melanoma Patients Switched to Type 1 by IL-12p70 mRNA-Transfected Dendritic Cells. Cancer Research. 68:9441-50, 2008. 7. Skoberne, M., Yewdall, A.W, Bahjat, KS, Godefroy, E., Lauer P., Lemmens, E., Liu W., Leong M., Dubensky, T.W., Brockstedy, D.G., Bhardwaj, N. KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of anti-tumor immunity. J. Clin Invest. 118(12): 3990-4001, 2008. 8. Bogunovic, D., O’Neill, D.W., Belitskaya-Levy, I., Vacic, V., Yu, Y., Adams, S., Darvishian, F., Berman, R., Shapiro, R., Pavlick, A., Lonadri, S., Zavadil, J., Osman, I. and Bhardwaj N. Immune profile and mitotic index of metastatic melanoma lesions enhance TNM staging in predicting patient survival. PNAS 106 (48) 20429-20434.2009. 9. Godefroy, E., Manches, O., Dreno, B, Labarriere, N., Goldberg, J., Guilloux, Y., Jotereau, F., Bhardwaj, N., Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory TH2 cells via an IL-12- and OX40Ldependent pathway. Cancer Cell. 19(3):333-46. 2011. 10. Gaziel-Sovran A, Segura MF, Di Micco R, Collins MK, Hanniford D, Vega-Saenz de Miera E, Rakus JF, Dankert JF, Shang S, Kerbel RS, Bhardwaj N, Shao Y, Darvishian F, Zavadil J, Erlebacher A, Mahal LK, Osman I, Hernando E. miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell. 12;20(1):104-18. 2011 11. Bogunovic, D., Manches, O., Yewdall, A., Salazar, A.M.,

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Marie, I., Levy, D.E., and Bhardwaj, N. TLR4 engagement during TLR3-induced proinflammatory signaling in dendritic cells promotes IL-10-mediated suppression of antitumor immunity. Cancer Res. 71(16): 5467-76 2011. 12. Bhardwaj, N., Gnjatic, S. Sawhney, and N.B. TLR Agonists: Are They Good Adjuvants? Cancer J.16 (4): 382–391. 2010. 13. Niardello, T., Jungbluth, A., Mei, A., DiLiberto, M., Huang, X., Dabrowski, A., Andrade, V.C.C., Wasserstrum, R., Ely, S., Niesvizky, R., Pearse, R., Coleman, M., Jayabalan, D., Bhardwaj, N., Old, L.J., Chen-Kiang, S. and Cho, H.j. MAGEA inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of surviving. Clin Can Res.17(13):4309-19, 2011. 14. Godefroy, E., Bhardwaj, N. Dysregulation of anti-tumor immunity by the matrix metalloproteinase-2. OncoImmunol. 1:1, 1-3, 2012. 15. Ott, PA., Henry, T., Baranda, SJ., Frleta, D., Manches, O., Bogunovic, D., Bhardwaj, N. Inhibition of both BRAF and MEK in BRAFV600E melanoma restores compromised Dendritic Cell (DC) function while having differential direct effects on DC properties Cancer Immunol Immunotherapy. 2013 Apr; 62(4): 811-22. doi:10.1007/s00262-012-1389-z. Epub 2013 Jan 10. 16. Miller, E,. Bhardwaj, N. A Bloody Mess: Dendritic Cells Use Hemophagocytosis to Regulate Viral Inflammation Immunity. 2013 Sep 19; 39 (3): 429-31. doi: 10.1016/j.imuni.2013.08.024. 17. Godfroy, E., Manches, O., Dreno, B., Labarriere, N., Goldberg, J., Guilloux, Y., Jotereau, F., Bhardwaj, N., Merad, M. Activation of Toll-like receptor-2 endogenous matrix metalloproteinase-2 modulates dendritic cell-mediated inflammatory responses. Immunity In Revision.

BIOGRAPHICAL SKETCH NAME Blander, Julie Magarian EDUCATION/TRAINING INSTITUTION AND LOCATION American University of Beirut, Beirut, Lebanon University of California Los Angeles, Center for the Health Sciences, Los Angeles, CA University of Pittsburgh School of Medicine, Department of Molecular Genetics and Biochemistry, Pittsburgh, PA Yale University School of Medicine, Department of Immunobiology, New Haven, CT A. Personal Statement My previous work and training in the laboratories of Olivera Finn, Charles Janeway and Ruslan Medzhitov have allowed me to gain extensive experience in tumor immunology, CD4 and CD8 T cell differentiation in mouse and human systems, DC biology, phagocytosis, and antigen presentation, as well as dissection of Toll-like receptor and Nod-like receptor signaling pathways. Our studies have led to several high impact publications, and have made significant impact in the fields of innate and adaptive immunity. B. Positions and Honors Positions and Employment 1986-1988 Clinical Laboratory Assistant, Department of Laboratory Medicine, Central Specimen Processing, University of California Los Angeles, Center for the Health Sciences. 1988-1991 Clinical Laboratory Technologist, Department of Laboratory Medicine, Clinical Virology Laboratory, University of California Los Angeles, Center for the Health Sciences.

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POSITION TITLE Associate Professor DEGREE B.S.

Ph.D.

YEAR(s) 1986

FIELD OF STUDY Health Sciences

1988

Clinical Laboratory Science

1997

Immunology

1997-2001

Immunology

1991-1997 Doctoral Candidate, Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Mentor: Olivera J. Finn, Ph.D. 1997-1999 Postdoctoral Associate, Section of Immunobiology, Howard Hughes Medical Institute & Yale University School of Medicine, Mentor: Charles A. Janeway, Jr., M.D. 1999-2001 Postdoctoral Associate, Section of Immunobiology, Yale University School of Medicine, Mentor: Ruslan M. Medzhitov, Ph.D. 2002-2005 Associate Research Scientist, Section of Immunobiology, Yale University School of Medicine, Laboratory of Ruslan M. Medzhitov, Ph. D. 2006-2010 Assistant Professor, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine. 2011-present Associate Professor, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine. Honors and awards

1983-1986 Dean’s Honor List, American University of Beirut. 1985 Calouste Gulbenkian Foundation Scholar. 1985 Bachelor of Science, with distinction. 1992 Winner of the U.S. Department of Education’s Graduate Assistance in Areas of National Need (GAANN), Women in Science Program Award. 1997-1999 Howard Hughes Medical Institute doctoral fellow. 2003 J. V. Satterfield Arthritis Investigator Award (distinction for highest score). 2006 May 2006 Nature top ten, Nature 2006, 440:808-12 2006-2008 Faculty of 1000 all time Top 10 in all Biology, F1000 factor 11.6 for Nature 2006, 440:808-12. 2006-present Faculty of 1000 all time Top 10 in Immunology F1000 factor 11.6 for Nature 2006, 440:808-12. 2007 Searle Scholar. 2009 Howard Hughes Medical Institute Early Career Scientist Competition Semifinalist. 7% applicant pool selected. 2009 American Cancer Society Research Scholar Award. 2009 G. Jeanette Thorbecke Award. 2010 Irma T. Hirschl and Monique Weill-Caulier Scholar Award. 2010 Harold and Golden Lamport Basic Research Award. 2011 Burroughs Wellcome Trust Fund Investigators in the Pathogenesis of Infectious Disease Award. 2011 MSSM Faculty Council Junior Faculty Award for Academic Excellence. 2014 Leukemia and Lymphoma Society Scholar Award. B. Selected Publications (out of a total of 47) 1. Nair-Gupta, P., Baccarini, A., Tung, N., Seyffer, F., Florey, O., Huang, Y., Banerjee, M., Overholtzer, M., Roche, P.A., Tampé, R., Brown, D.B., Amsen, D., Whiteheart, S.W., and J. M. Blander. TLR Signals Induce Phagosomal MHC-I Delivery

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from the Endosomal Recycling Compartment to Allow Crosspresentation. 2014 Cell in press. Moretti, J. and J. M. Blander. Insights into phagocytosiscoupled activation of pattern recognition receptors and inflammasomes. 2014. Current Opinion in Immunology. 26:100-110. Vabret, N. and J. M. Blander. Sensing microbial RNA in the cytosol. 2014. Frontiers in Immunology 4:468. Nair-Gupta, P. and J. M. Blander. An updated view of the intracellular mechanisms regulating cross-presentation. 2013. Frontiers in Immunology 4:401. Shan, M., Gentile, M. Yeiser, J.R., Walland, A.C., Bornstein, V.U., Chen, K., He, B., Cassis, L., Bigas, A., Cols, M., Comerma, L., Huang, B., Blander, J.M., Xiong, H., Mayer, L., Berin, C., Augenlicht, L.H., Velcich, A., and A. Cerutti. Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals. 2013. Science 342: 447-453 Mourao-Sa, D., Roy, S. and J. M. Blander. Vita-PAMPs: signatures of microbial viability. 2013 Advances in Experimental Medicine and Biology 785:1-8. Agudo, J., Ruzo, A., Kitur, K. Sachidanandam, R., Blander, J. M. and B. D. Brown. A TLR and Non-TLR mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade. 2012. Molecular Therapy. 12:2257-2267. Garaude, J., Kent, A., van Rooijen, N. and J. M. Blander. Superior immunotherapy by simultaneous targeting of Tolllike and Nod-like receptors. 2012. Science Translational Medicine. 4(120):120ra16. Blander, J. M. and L. E. Sander. Beyond pattern recognition: Five immune checkpoints for scaling the microbial threat. 2012. Nature Reviews Immunology, 12:215-225.

10. Blander, J. M., M. B. Torchinsky, and L. Campisi. Revisiting

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17.

18.

the link between infection and autoimmune disease with commensals and T helper 17 cells. 2012. Immunological Research. 54:50-68. [Epub ahead of print 2012 March 30]. Nair, P., Amsen, D., and J. M. Blander. Coordination of incoming and outgoing traffic in antigen-presenting cells by pattern recognition receptors and T cells. 2011. Traffic 12:1669-76. Sander, L. E., Davis, M. J., Boekschoten, M. V., Amsen, D., Dascher, C. C., Ryffel, B., Swanson, J. A., Müller, M., and J. M. Blander. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. 2011. Nature 474:385-389. [Epub 2011 May 22]. Blander, J. M. Apoptosis and TH17 cell differentiation. Textbook entitled: “TH17 cells in Health and Disease.” Jiang, Shuiping (Ed.), 1st Edition, 2011, XIV:63-106. Springer New York Publishers. Brereton, C. F. and J. M. Blander. The unexpected link between infection-induced apoptosis and a Th17 immune response. 2011. Journal of Leukocyte Biology. 4:565-76. Brereton, C. F. and J. M. Blander. Responding to infection and apoptosis – A task for TH17 cells. 2010. Annals of the New York Academy of Sciences 1209:56-67. Torchinsky, M. B., Garaude, J, and J. M. Blander. Infection and apoptosis as a combined inflammatory trigger. 2010. Current Opinion in Immunology. 22:55-62. Torchinsky, M. B. and J. M. Blander. T helper 17 cells: discovery, function, and physiological trigger. 2010. Cellular and Molecular Life Sciences. 67:1407-21 . Mosoian, A., Teixeira, A., Burns, C. S., Sander, L. E., Gusella, L., He, C., Blander, J. M., Klotman, P. and M. Klotman. Prothymosin-a Inhibits HIV-1 via Toll-like Receptor 4

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19.

20.

21.

22.

23.

24.

25.

26.

Mediated Type I Interferon Induction. 2010. Proceedings of the National Academy of Sciences. 107:10178-83. Torchinsky M. B., Garaude J., Martin A. P., and J. M. Blander. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. 2009. Nature. 458:78-82. Blander, J.M. and R. Medzhitov. On phagosome maturation and antigen presentation. 2006. Nature Immunology 7:10291035. Blander, J. M. and R. Medzhitov. Toll-dependent selection of microbial antigens for presentation by dendritic cells. 2006. Nature 440:808-812. Blander, J. M. and R. Medzhitov. Regulation of phagosome maturation by signals from Toll-like receptors. 2004. Science 304:1014-1018 (Cover article). Amsen, D., Blander, J. M., Lee, G. R., Tanigaki, K., Honjo, T., and R. A. Flavell. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. 2004. Cell, 117:515-526. Blander, J. M., Sant’Angelo, D. B., Metz, D., Kim, S.-W., Flavell, R. A., Bottomly, K., and C. A. Janeway. A pool of memory-like CD4 T cells contains effector memory precursors. 2003. Journal of Immunology, 170:2940-2948. Blander, J. M., Sant’Angelo, D. B., Bottomly, K., and C. A. Janeway. Alteration at a single amino acid residue in the T cell receptor α chain complementarity determining region 2 changes the differentiation of naïve CD4 T cells in response to antigen from T helper cell type 1 (Th1) to Th2. 2000. Journal of Experimental Medicine, 191:2065-2073. Magarian-Blander, J., Ciborowski, P., Hsia, S., Watkins, S. C., and O. J. Finn. Intercellular and intracellular events following the MHC-unrestricted TCR recognition of a tumor-specific peptide epitope on the epithelial antigen MUC1. 1998. Journal of Immunology, 160:3111-3120.

BIOGRAPHICAL SKETCH NAME Bona, Constantin EDUCATION/TRAINING INSTITUTION AND LOCATION School of Medicine and Pharmacy, Bucharest, Romania Post Graduate School of Medicine, Bucharest, Romania Paris University, Paris, France A. Personal Statement The focus of my research was to determine the structure of mutated fibrillin-1 gene in TSK mice which develop a scleroderma-like syndrome, to demonstrate whether mutated fibrillin-1 gene is translated, and to determine whether mutated fibrillin-1 gene represents TSK mutation. My laboratory’s goal was to carry out modern immunological research and develop an immunology research program at Mount Sinai. B. Positions and Honors Positions 1960-1968 Head of Immunochemistry Laboratory, Cantacuzino Institute, Bucharest, Romania 1968-1970 Scientist, Claude Bernard, Paris, France 1970-1971 Research Scientist, National Institute for Medical Science, Paris, France 1971-1975 Research Scientist, CNRS and Pasteur Institut, Paris, France 1975-1977 Senior Investigator, CNRS and Pasteur Institut, Paris, France

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POSITION TITLE Professor of Microbiology DEGREE

MM/YY

FIELD OF STUDY

M.D.

1958

Medicine

Ph.D.

1968

Cell Biology

Dsc

1972

Cell Biology

1977-1979 Visiting Scientist, Laboratory of Immunology, MAID, NIH, Bethesda, MD 1979-1981 Associate Professor, Department of Microbiology, Mount Sinai School of Medicine, NY 1982-2011 Professor, Department of Microbiology, Mount Sinai School of Medicine, NY 1985 Visiting Professor, Department of Biology, MIT, Cambridge, MA (Jan – July) 1996-1997 Visiting Professor, Institute of Genetics and Molecular Biology, Kyoto, Japan 2011-present Professor Emeritus, Icahn School of Medicine at Mount Sinai, NY Scientific Societies 1968 Elected Member of International Society of Cell Biology Elected Member of Board of Governors of the European Cell Biology Organization 1969 Elected Member of French Society of Immunology, Paris Elected Member of Royal Microscopial Society, Oxford Elected Member of Reticuloendothelial Society, USA

Nominated Member of the Board of European Group for the Study of Lysosomes, Louvain 1970 Elected Member of Royal Society of Medicine, London 1971 Elected Member of French Society of Electron Microscopy, Paris 1973 Elected Member of British Society of Immunology 1978 Elected Member of American Association of Immunology 1980 American Society of Zoologists The New York Academy of Sciences 1985 Elected Member of The Harvey Society 1991 Honorary Member of Romanian Immunology Society 1992 Elected Member of Romanian Academy 1998 President of Romanian Society for Immunology 2004 American Academy of Microbiology Professional Organizations Ad hoc reviewer National Science Foundation (Cell Physiology Program) American Cancer Society NIH – Allergy and Immunity Study Section, Program Project: Autoimmunity National Fund for Scientific Research, Belgium Foundation for Medical and Health Research Council, Canada Arthritis Foundation, Devil’s Bag Award Medical Council, Canada National Cancer Institute National Institute of Allergy and Infectious Diseases Veteran Administration National Health and Medical Research Council, Commonwealth of Australia Canadian Arthritis Foundation US-Israel BiNational Science Foundation, Jerusalem

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1996 Advisory Council of NIAID – Ad hoc member 1987-1990 Member of Basic Virology, Immunology and Pathogenesis of Acquired Immunodeficiency Syndrome NIH Study Section 1989-1992 Member of Immunology and Immunotherapy – Study Section of American Cancer Society 1997 Member of Japan Prize nomination Committee 2000 Member of The Royal Swedish Academy for nomination for Crafoord Prize for Rhematoid arthritis General Motors – Sloan Kettering and Mott Prize Member of Scleroderma Foundation Grant Review Panel Editorial Activity 1980-1985 Chief Editor, Modern Concept of Immunology 1985-1996 Chief Editor, International Journal of Microbiology 1986-2006 Chief Editor, International Reviews in Immunology 1994-2000 Chief Editor, Viral Immunology 1987-1992 Section Editor, Journal of Immunology 1991-2000 Regional Editor USA, AutoImmunity 1982-1987 Associate Editor, Journal of Immunology 1987-1996 Associate Editor, Aging Immunobiology and Infectious Diseases 1981-1986 Editorial Board, American Journal of Reproductive Immunology 1988-1996 Editorial Board, Cellular Immunology 1986-1994 Editorial Board, Viral Immunology 1988-present Editorial Board, Encyclopedia of Immunology 1991-1996 Editorial Board, Advances in Neuroimmunology 1981-1986 Editorial Board, Journal of Reproductive Immunology 1991-2004 Editorial Board, Molecular Immunology 1991-present Editorial Board, Critical Reviews in Immunology

1981-1990 Editorial Board, Journal of Experimental Medicine 1996-present Editorial Board, Research Trends 1996-2010 Editorial Board, Human Immunology 1999-present Editorial Board, Cell Research 2001-present Editorial Board, J. Cell. Molec. Med 2003-present Editorial Board, J. of Clin. Immunol Scientific Boards Alliance Pharmaceutical Inc. (La Jolla, CA) Immune Response Corp. (La Jolla, CA) IDEC. (La Jolla, CA) Alatrex (Edmonton, Canada) Institute Cantacuzino (Bucharest, Romania) C. 15 Most Recent Publications 1. Lemaire R, Farina G, Kissin E, Shipley JM, Bona C, Korn JH, Lafyatis R. Mutant fibrillin 1 from tight skin ice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I . Arthritis Rheum. 2004 Mar;50(3):915-26. PubMed PMID: 15022335. 2. Kodera T, Radu D, McGaha T, Zwolo P, Stoica C, Cheroute H, Pollock RR, Bona C. Cellular and molecular studies of B cells exhibiting reverse somatic mutation throughout life. Genes Cells. 2004 Nov;9(11):1005-16. PubMed PMID: 15507113. 3. Zhou X, Tan FK, Milewicz DM, Guo X, Bona CA, Arnett FC. Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the "scleroderma phenotype". J Immunol. 2005 Oct 1;175(7):4555-60. PubMed PMID: 16177099. 4. Preda I, McEvoy RC, Lin M, Bona CA, Rapaport R, Brumeanu TD, Casares S. Soluble, dimeric HLA DR4-peptide chimeras: an approach for detection and immunoregulation of human type-1 diabetes. Eur J Immunol. 2005 Sep;35(9):2762-75. PubMed PMID: 16106371.

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5. Preda-Pais A, Stan AC, Casares S, Bona C, Brumeanu TD. Efficacy of clonal deletion vs. anergy of self-reactive CD4 Tcells for the prevention and reversal of autoimmune diabetes. J Autoimmun. 2005 Aug;25(1):21-32. PubMed PMID: 16005609. 6. Bhogal RK, Stoica CM, McGaha TL, Bona CA. Molecular aspects of regulation of collagen gene expression in fibrosis. J Clin Immunol. 2005 Nov;25(6):592-603. Review. PubMed PMID: 16380822. 7. Bhogal RK, Bona CA. B cells: no longer bystanders in liver fibrosis. J Clin Invest. 2005 Nov;115(11):2962-5. PubMed PMID: 16276407; PubMed Central PMCID: PMC1265880. 8. Phillips WJ, Smith DJ, Bona CA, Bot A, Zaghouani H. Recombinant immunoglobulin-based epitope delivery: a novel class of autoimmune regulators. Int Rev Immunol. 2005 Sep-Dec;24(5-6):501-17. Review. PubMed PMID: 16318992. 9. Bot A, Smith D, Phillips B, Bot S, Bona C, Zaghouani H. Immunologic control of tumors by in vivo Fc gamma receptor-targeted antigen loading in conjunction with double-stranded RNA-mediated immune modulation. J Immunol. 2006 Feb 1;176(3):1363-74. PubMed PMID: 16424163. 10. Brumeanu TD, Preda-Pais A, Stoica C, Bona C, Casares S. Differential partitioning and trafficking of GM gangliosides and cholesterol-rich lipid rafts in thymic and splenic CD4 T cells. Mol Immunol. 2007 Jan;44(4):530-40. Epub 2006 Apr 4. PubMed PMID: 16597465. 11. Casares S, Lin M, Zhang N, Teijaro JR, Stoica C, McEvoy R, Farber DL, Bona C, Brumeanu TD. A peptide-major histocompatibility complex II chimera favors survival of pancreatic beta-islets grafted in type 1 diabetic mice.

Transplantation. 2008 Jun 27;85(12):1717-25. doi: 10.1097/TP.0b013e31817752cc. PubMed PMID: 18580462. 12. Bhogal RK, Bona CA. Regulatory effect of extracellular signal-regulated kinases (ERK) on type I collagen synthesis in human dermal fibroblasts stimulated by IL-4 and IL-13. Int Rev Immunol. 2008;27(6):472-96. doi:10.1080/08830180802430974. PubMed PMID: 19065352. 13. Nazarov-Stoica C, Surls J, Bona C, Casares S, Brumeanu TD. CD28 signaling in T regulatory precursors requires p56lck and rafts integrity to stabilize the Foxp3 message. J Immunol. 2009 Jan 1;182(1):102-10. PubMed PMID: 19109140.

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14. Duncan B, Nazarov-Stoica C, Surls J, Kehl M, Bona C, Casares S, Brumeanu TD. Double negative (CD3+ 4- 8-) TCR alphabeta splenic cells from young NOD mice provide longlasting protection against type 1 diabetes. PLoS One. 2010 Jul 2;5(7):e11427. doi: 10.1371/journal.pone.0011427. PubMed PMID: 20625402; PubMed Central PMCID: PMC2896421. 15. Lin M, Stoica-Nazarov C, Surls J, Kehl M, Bona C, Olsen C, Brumeanu TD, Casares S. Reversal of type 1 diabetes by a new MHC II-peptide chimera: "Single-epitope-mediated suppression" to stabilize a polyclonal autoimmune T-cell process. Eur J Immunol. 2010 Aug;40(8):2277-88. doi: 10.1002/eji.200940094. PubMed PMID: 20540111.

BIOGRAPHICAL SKETCH NAME Brody, Joshua

POSITION TITLE Assistant Professor

EDUCATION/TRAINING INSTITUTION AND LOCATION

DEGREE

MM/YY

Harvard university, Boston Massachusetts

AB

1996

S.U.N.Y. Stony Brook, Stony Brook, MY Yale New Haven Hospital Stanford University Medical Center – Pathology Stanford University Medical Center – Medicine

MD

2000

FIELD OF STUDY Molecular & Cellular bio Medicine

2003-2004 2004- 2009

Tumor Immunology Medical Oncology

A. Personal Statement I have extensive experience in conducting trials of intratumoral TLR-based in situ vaccination and developing immune correlative studies: NCT00185965 {Brody et al., J, Clin Oncol 2010}, NCT00226993{Kim et al., Blood 2012}, NCT00880581, and NCT01396018. As Director of the Lymphoma Immunotherapy Program at Mount Sinai School of Medicine, I also have available resources and a substantial cohort of eligible patients to rapidly and fully accomplish the goals of the proposed study. The Brody Lab focuses on pre-clinical and clinical development of novel vaccine and adoptive T cell transfer approaches to treat patients with lymphoma and hematologic malignancies. Specifically, current projects including work on an in vitro high throughput combinatorial survey of a panel of TLR agonists for activation of PBMC, cutaneous APC, and B-cell lymphomas- this project has potential application to the proposed Research Plan if we observe insufficient activation of intratumoral Flt3L-recruited DC using poly-ICLC, future iterations can utilize the alternatives determined to be more effective from this project B. Positions and Honors

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Faculty 12/2011 – present: Assistant Professor, Department of Medicine, Division of Hematology & Medical Oncology director, Lymphoma Immunotherapy Program director, Mount Sinai – St. Lukes-Roosevelt – Beth Israel MultiDisciplinary Lymphoma Tumor Board member, Tisch Cancer Institute member, Immunology Institute member, Mount Sinai School of Medicine Institutional Review Board- Board D reviewer, Mount Sinai School of Medicine Protocol Review and Monitoring Committee Research Experience 2004-12/2011: Post-doctoral fellow in the lab of Ronald Levy, Stanford Divison of Oncology. Development of immunotherapy for lymphoma. 2003-4: Recipient of Stanford Dept of Immunology NIH funded post-doctoral research fellowship mentored by Dr. Edgar Engleman and Dr. Jonathan Pollack.

Identification of Novel Prostate Adenocarcinoma-Produced Dendritic Cell Suppressors by Gene Expression Profiling Focus on tumor-induced inhibition of monocyte derived DC IL-12 production and surface co-stimulatory molecule expression in response to Toll-Like Receptor agonists 1998: Proposal design at S.U.N.Y. S.B. Dept. of Biochemistry with Dr. Sanford Simon Development of plasmid encoding single-chain, intracellularly expressed monoclonal antibodies under the control NK- κB. Focus on anti-NF-κB scFv cDNA isolation from B cell library phage display selection. 1994-6: Research associate at Dana Farber Cancer Institute Department of Tumor Immunology with Dr. Christopher Rudd Signaling and trafficking of the CD28 Costimulatory Molecule. Activation mechanisms of the HIV-LTR promoter by CD28. Focus on correlation of CD28 costimulatory function and trafficking stage in wild-type and PI3-K binding mutants. Also published in Harvard University Dept. of Molecular and Cellular Biology archival collection. 1994: Research associate at NYU Dept. of Biochemistry with Dr. Michel Blumenfeld Analysis of cis- and trans- elements of the keratin 17 and involucrin promoters. Focus on preparation of the promoters for these markers and isolation of the trans- binding elements for the purpose of determining transcription factors culprit in the malignant transformation. Other Experience and Professional Memberships 2013 --Alliance For Clinical Trials in Oncology. 2012 --Society for the Immunotherapy of Cancer 2007 --American Association of Cancer Research, associate member 95

2006 --Mantle Cell Lymphoma Consortium, member 2004 --American Society of Clinical Oncology, associate member 2004 --American Society of Hematology, associate member Honors and Awards 2011 Society for Immunotherapy of Cancer Presidential Award (SITC 26th Annual Meeting) 2011 Swiss Cancer League Award - top abstract submitted to 2011 International Conference on Malignant Lymphoma 2011 ASCO Merit Award for top 100 abstracts submitted to 2011 Annual Meeting 2009 SUNY Stony Brook School of Medicine ‘Outstanding Recent Graduate’ 2008 ASCO Bradley Stuart Beller Award for highest ranking Annual Meeting abstract 2008 William Guy Forbeck Scholar Award – invited to present at 2008 Forum 2007 Division of Blood and Marrow Transplantation Program Project Grant co-Principal Investigator – Immune Therapies for non- Hodgkin’s Lymphoma 2007 ACGT co-Investigator $1M Fund for Advancement Grant A Gene-Engineered Tumor Vaccine with Stem Cell Transplant for Mantle Cell Lymphoma 2007 Leukemia & Lymphoma Society - Special Fellow in Clinical Research (deferred) 2005 Attendee – ACCR Methods in Clinical Cancer Research, Vail, CO 2003 Nominated for Chief Residency, Yale New Haven Hospital, Deptartment of Internal Medicine, New Haven, CT (deferred) 2000 Valedictorian Commencement Address, Stony Brook, NY

1998 Early induction into Alpha Omega Alpha (AOA) Honor Society, Stony Brook, NY C. Selected Peer-Reviewed Publications 1. Rezvani K, Brody JD, Kohrt HE, Logan AC, Advani R, Czerwinski DK, Weng WK, Negrin RS, Carlton V, Faham M, Levy R, Barrett J. Cancer Vaccines and T Cell Therapy. Biol Blood Marrow Transplant. 2012 Oct 3. 2. Ng PP, Jia M, Patel KG, Brody JD, Swartz JR, Levy S, Levy R. A vaccine directed to B cells and produced by cell-free protein synthesis generates potent antilymphoma immunity. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14526-31. 3. Kohrt HE, Houot R, Marabelle A, Cho HJ, Osman K, Goldstein M, Levy R, Brody J. Combination strategies to enhance antitumor ADCC. Immunotherapy. 2012 May;4(5):511-27. 4. Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, Morales A, Abdulla F, Xing L, Navi D, Tibshirani RJ, Advani RH, Lingala B, Shah S, Hoppe RT, Levy R. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood. 2012 Jan 12;119(2):355-63. 5. Brody J, Kohrt H, Marabelle A, Levy R. Active and passive immunotherapy for lymphoma: proving principles and improving results. J Clin Oncol. 2011 May 10;29(14):1864-75. 6. Kohrt HE, Houot R, Goldstein MJ, Weiskopf K, Alizadeh AA, Brody J, Müller A, Pachynski R, Czerwinski D, Coutre S, Chao MP, Chen L, Tedder TF, Levy R. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood. 2011 Feb 24;117(8):2423-32. 7. Goldstein MJ, Varghese B, Brody JD, Rajapaksa R, Kohrt H, Czerwinski DK, Levy S, Levy R. A CpG-loaded tumor cell vaccine induces antitumor CD4+ T cells that are effective in

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8.

9. 10.

11.

12. 13. 14. 15.

adoptive therapy for large and established tumors. Blood. 2011 Jan 6;117(1):118-27. Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, Kim YH, Hoppe RT, Knox SJ, Shin LK, Wapnir I, Tibshirani RJ, Levy R. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol. 2010 Oct 1;28(28):4324-32. Brody J, Levy R. Lymphoma immunotherapy: vaccines, adoptive cell transfer and immunotransplant. Immunotherapy. 2009 Sep;1(5):809-24. Brody JD, Goldstein MJ, Czerwinski DK, Levy R. Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors. Blood. 2009 Jan 1;113(1):85-94. Brody JD, Advani R, Shin LK, Bingham DB, Rosenberg SA. Splenic diffuse large B-cell lymphoma in a patient with type 1 Gaucher disease: Diagnostic and therapeutic challenges. Ann Hematol. 2006 Nov;85(11):817-20. Brody J, Advani R. Treatment of mantle cell lymphoma: current approach and future directions. Crit Rev Oncol Hematol. 2006 Jun;58(3):257-65.. Engleman EG, Brody J, Soares L. Using signaling pathways to overcome immune tolerance to tumors. Sci STKE. 2004 Jul 6;2004(241):pe28. Brody JD, Engleman EG. DC-based cancer vaccines: lessons from clinical trials. Cytotherapy. 2004;6(2):122-7. Céfaï D, Schneider H, Matangkasombut O, Kang H, Brody J, Rudd CE. CD28 receptor endocytosis is targeted by mutations that disrupt phosphatidylinositol 3-kinase binding and costimulation. J Immunol. 1998 Mar 1;160(5):2223-30.

BIOGRAPHICAL SKETCH NAME Brown, Brian D. EDUCATION/TRAINING INSTITUTION AND LOCATION University of Guelph, Guelph, Ontario, Canada Queen’s University, Kingston, Ontario, Canada Hospital San Raffaele, Milan, Italy A. Personal Statement My laboratory is focused on identifying factors that control the innate immune system in different disease conditions, and in response to particular drugs, including gene-based medicines. In collaboration with the Merad lab in the Mount Sinai Immunology Institute, we have carried out detailed work to decipher the transcriptional programs that control dendritic cell development and function, which included profiling and analysis of more than 200 different populations of immune cells (Miller et al. Nature Immunology 2012), and to identify the mechanisms involved in the host response to HIV and HIVderived vectors (Brown et al. Blood 2007, Agudo et al. Molecular Therapy 2012). More recently, we identified a new pathway controlling the type I interferon response to pathogen-associated nucleic acids and HIV, which involves the microRNA miR-126, and the main VEGF receptor, VEGFR2 (Agudo et al. Nature Immunology 2014). We are now investigating how miR-126/VEGFR2 control of the innate immune system impacts tumor growth. In addition to our work on innate immunity, we are studying some of the fundamental aspects of microRNA biology. Specifically, we are trying to understand how microRNAs and their targets interact and the consequences of this interaction. We were amongst the first to show that the target of a   97

POSITION TITLE Associate Professor DEGREE B.Sc. Ph.D.

MM/YY 1993 - 1997 1998 - 2003 2003 - 2007

FIELD OF STUDY Biomedical Science Pathology Molecular Medicine

microRNA can ‘sponge’ the microRNA and inhibit its activity (Brown et al. Nat Biotech 2007). This finding led to the development of microRNA sponge/decoy vectors, which is a seminal technology that enables inhibition of a microRNA within a cell and loss-of-function analysis (Brown and Naldini. Nat Rev Gen 2009). We subsequently uncovered one of the mechanisms responsible for the sponging phenomenon, which involves a negative feedback mechanism whereby target regulation results in uridylation of a microRNA and this mark accelerates the microRNA’s rate of decay (Baccarini et al. Curr Biol 2011). We are now working to understand how endogenous sponging that is mediated by a newly discovered class of RNAs, called circular RNAs, impacts cell regulation and oncogenesis. B. Positions and Honors Academic Appointments 2013 – Present Associate Professor, Icahn School of Medicine at Mount Sinai, New York, NY Department of Genetics and Genomic Sciences 2012 – Present Faculty, Tisch Cancer Institute 2012 – Present Faculty, Diabetes, Obesity and Metabolism Institute 2012 – Present Faculty, Mindich Child Health and Development Institute

 

2009 – Present Faculty, Mount Sinai Immunology Institute 2008 – 2012 Assistant Professor, Mount Sinai School of Medicine, New York, NY Department of Genetics and Genomic Sciences Postgraduate and Postdoctoral Training 2003 – 2007 Postdoctoral, Telethon Institute for Gene Therapy, Milan, Italy Mentor: Drs. Luigi Naldini and Maria Grazia Roncarolo 1997 – 2003 Doctoral, Department of Pathology, Queen’s University, Kingston, Ontario Mentor: Dr. David Lillicrap Other Experience and Professional Memberships 2013 – Present Editorial Board, Molecular Therapy 2010 – Present American Society of Gene and Cell Therapy Oligonucleotide Therapy Committee 2010 – Present American Society of Gene and Cell Therapy Educational Committee 2009 – Present Associate Faculty Member, Faculty of 1000 1998 – Present Member, American Society of Gene and Cell Therapy Peer Review (selected) 2014 NIH Study Section Committee: Molecular and Cellular Hematology (MCH), ad hoc reviewer. 2012 Flanders Research Foundation 2011 Swiss National Science Foundation 2011 NIH Study Section Committee: Special Emphasis Section on Type I Diabetes 2011 NIH Study Section Committee: Special Emphasis on viral microRNAs 2010 NIH Study Section Committee: Innate Immunity and Inflammation (III), ad hoc reviewer.   98

2009 Scientific Committee of the Association Française contre les Myopathies 2003 – Present Reviewer: Blood, Current Biology, EMBO Reports, Gene Therapy, Genome Biology, Genome Research, Human Gene Therapy, Immunity, International Journal of Cancer, Journal of Biomedicine and Biotechnology, Journal of Virology, Molecular Therapy, Nature, Nature Biotechnology, Nature Reviews Genetics, Nature Methods, Nucleic Acids Research, PLoS One, PLoS Pathogens, Stem Cells. C. Selected Peer-reviewed Publications (15 of 41) 1. Agudo JA, Ruzo A, Tung N, Salmon H, Leboeuf M, Hashimoto D, Becker C, Garrett-Sinha LA, Baccarini A, Merad M, Brown BD. The microRNA-126-VEGFR2 axis controls the innate response to pathogen-associated nucleic acids. Nature Immunology. 2014 Jan;15(1):54-62. 2. Parikh A, Lee C, Joseph P, Marchini S, Baccarini A, Kolev V, Romualdi C, Fruscio R, Shah H, Wang FQ, Mullokandov G, Fishman D, D'Incalci M, Rahaman J, Kalir T, Redline R, Brown BD, Narla G, and DiFeo A. microRNA-181a plays a critical role in ovarian cancer progression through the regulation of epithelial-mesenchymal transition. Nature Communications. 2014 Jan 7;5:2977. 3. Agudo JA, Ruzo A, Kitur K, Sachidanandam R, Blander JM, Brown BD. A TLR and non-TLR mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade. Molecular Therapy. 2012 Dec;20(12):2257-67. 4. Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, Pandey G, Leboeuf M, Elpek KG, Helft J, Hashimoto D, Chow A, Price J, Greter M, Bogunovic M, Bellemare-Pelletier A, Frenette PS, Randolph GJ, Turley SJ, Merad M. Deciphering the transcriptional network of the DC lineage. Nature Immunology. 2012 Jul 15;13(9):888-899.

5. Mullokandov G, Baccarini A, Ruzo A, Jayaprakash AD, Tung N, Israelow B, Evans MJ, Sachidanandam R, Brown BD. miRNA sensor and decoy libraries provide insight into miRNA function and concentration requirements. Nature Methods. 2012 Jul 1;9(8):840-6. 6. Chow A, Brown BD, Merad M. Novel tools to dissect the mononuclear phagocyte system. Nature Reviews Immunology. 2011 Oct 25;11(11):788-98. 7. Jayaprakash A, Jabado O, Brown BD, Sachidanandam R. Identification and remediation of biases in the activity of RNA-ligases in deep sequencing of small RNAs. Nucleic Acids Research. 2011 Nov 1;39(21):e141. 8. Baccarini A, Chauhan H, Gardner TJ, Jayaprakash A, Sachidanandam R, Brown BD. Kinetic analysis reveals the fate of a microRNA following target regulation in mammalian cells. Current Biology. 2011 Mar 8;21(5):369-76. 9. Annoni A*, Brown BD*, Cantore A, Sergi Sergi L, Naldini L, Roncarolo MG. In vivo delivery of a microRNA regulated transgene induces antigen-specific regulatory T cells and promotes immunological tolerance. Blood 2009 Dec 10;114(25):5152-61. *equal contribution. 10. Salerno E, Scaglione BJ, Coffman FD, Brown BD, Baccarini A, Fernandes H, Marti G, Raveche ES. Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity. Molecular Cancer Therapeutics. 2009 Sep;8(9):2684-92. 11. Brown BD, Naldini L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nature Reviews Genetics. 2009 Aug;10(8):578-85. 12. Brown BD, Gentner B, Cantore A, Colleoni S, Amendola M, Zingale A, Baccarini A, Lazzari G, Galli C, Naldini L.Endogenous microRNAs Can Be Broadly Exploited to Regulate Transgene Expression According to Tissue,   99

Lineage, and Differentiation State. Nature Biotechnology 2007 Dec;25(12):1457-1467. 13. Brown BD, Cantore A, Annoni A, Sergi Sergi L, Lombardo A, Della Valle P, D’Angelo A, Naldini L. A microRNA-regulated Lentiviral Vector Mediates Stable Correction of Hemophilia B Mice. Blood 2007 Dec 15;110(13):4144-52. 14. Brown BD, Sitia G, Annoni A, Hauben E, Sergi Sergi L, Zingale A, Roncarolo MG, Guidotti L, Naldini L. In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance. Blood 2007 April; 109(7): 2797-2805. 15. Brown BD, Venneri MA, Zingale A, Sergi Sergi L, Naldini L. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nature Medicine 2006 May;12(5):585-91.

BIOGRAPHICAL SKETCH NAME Burakoff, Steven James

EDUCATION/TRAINING INSTITUTION AND LOCATION Lehigh University, Bethlehem, PA Queens College, Flushing, NY Albany Medical College Albany, NY N.Y. Hospital-Cornell Med. Center, NY N.Y. Hospital-Cornell Med. Center, NY A. Personal Statement Dr. Burakoff is the Director of the Tisch Cancer Institute, and has extensive administrative experience, having served as Director of the New York University Cancer Institute (NYUCI) at the New York University School of Medicine (NYUSM) from 2000-2007, as well as the Director of the Skirball Institute of Biomolecular Medicine at New York University from 20002006; former Chair of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute from 1985-2000; and in his current position as a member of the external advisory boards of four NCI-designated cancer centers. He has been a member of the American Cancer Society’s Council of Extramural Grants, and sits on the Damon Runyon Cancer Research Foundation Board of Directors. Dr. Burakoff also has over 30 years of experience in immunological research. His research has focused on the role of the T cell in the immune response and he has been one of the most highly cited researchers in Immunology for over 25 years.

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POSITION TITLE Director, The Tisch Cancer Institute Lillian and Henry M. Stratton Professor of Cancer Medicine, Mount Sinai School of Medicine DEGREE B.A. M.A. M.D. Intern Resident

MM/YY 1964 1965 1970 1970-1971 1971-1973

FIELD OF STUDY Psychology Psychology Medicine Medicine Medicine

B. Positions and Honors Positions and Employment 1973-1976 Research Fellow in Pathology, Harvard Medical School, Boston, MA (Advisor: Dr. Baruj Benacerraf) 1976-1977 Fellow in Immunology, Rockefeller University, New York, NY (Advisor: Dr. Henry Kunkel) 1976-1977 Instructor in Pathology, Harvard Medical School 1977-1980 Assistant Professor of Pathology, Harvard Medical School 1980-1983 Assistant Professor of Pediatrics, Harvard Medical School 1980-1983 Associate Professor of Pediatrics, Harvard Medical School 1983-2000 Professor of Pediatrics, Harvard Medical School 1985-2000 Chair, Department of Pediatric Oncology, DanaFarber Cancer Institute 1995-2000 Ted Williams Senior Investigator, Dana-Farber Cancer Institute 1998-2000 Margaret M. Dyson Professor of Pediatrics, Harvard Medical School

2000-2006 Director, Skirball Institute of Biomolecular Medicine, New York University School of Medicine 2000-2007 Laura and Isaac Perlmutter Professor, New York University School of Medicine 2000-2007 Director, NYU Cancer Institute, New York University School of Medicine 2007- Director, The Tisch Cancer Institute (formerly the Mount Sinai Cancer Institute), Mount Sinai School of Medicine 2007- Professor of Medicine, Mount Sinai School of Medicine 2007- Professor of Oncological Sciences 2009- Lillian and Henry M. Stratton Professor of Cancer Medicine, Mount Sinai School of Medicine Honors, Societies and Service Activities: 1980-85 American Cancer Society Faculty Research Award; 1979-83 Member, Clinical Sciences Study Section, National Institutes of Health; 1983-87 American Cancer Society-Advisory Committee on Immunology and Immunotherapy; 1994-95 World AIDS Foundation; 1979-81 Associate Editor, Journal of Immunology; 1981- Editor, Immunologic Research; 1983-06; Editor, Cellular Immunology; 1981-85 Section Editor, Journal of Immunology; 1985-88 Editorial Board, Transplantation; 1992-94 Deputy Editor, Journal of Immunology; 1995-2002 Editorial Board, Biology of Blood and Marrow Transplantation. 19932002 Member, External Advisory Committee, Division of Clinical Sciences, Fred Hutchinson Cancer Institute; 1999-2003 Member, Publications Committee, American Association of Immunologists; 1994-2000 Board of Directors, The Medical Foundation; 1996-2000 Board of Trustees; Dana-Farber Cancer Institute; 2001- Scientific Advisory Board, Cold Spring Harbor Laboratory Cancer Center; 2003-Board of Directors Damon Runyon Foundation, 2005- Member, External Advisory Board Cancer Center, St. Jude Research Hospital, 2006- Starr Cancer

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Foundation; 2008- Melanoma Research Alliance; 2014AACR/SU2CJoint Scientific Advisory Board; Scientific Review Council Pershing Square Foundation; Alpha Omega Alpha, American Association of Immunologists; Transplantation Society; American Society of Hematology; American Society for Clinical Investigation; American Association of Physicians; ISI Highly Cited Researcher (1980-2008); 2002-Theobald Smith Alumni Lecture, Albany Medical College; 2003 Distinguished Alumni Award, Albany Medical College; 2003-SecretaryTreasurer, American Association of Immunologists; 2006-Lynne Cohen Foundation Award, 2009-American Association of Immunologists Lifetime Achievement Award; C. Selected Peer-reviewed Publications (Selected from 374 peer-reviewed publications) Additional recent publications of importance to the field (in chronological order) 1. Hollander, G.A., Zuklys, S., Morel, C., Mizoguchi, E., Mobisson, K., Simpson, S., Terhorst, C., Wishart, W., Golan, D.E., Bhan, A.K., and Burakoff, S.J.: Monoallelic expression of the Interleukin–2 locus. Science 1998; 279:2118-2121. 2. Irie, H.Y., Mong. M.S., Itano, A., Crooks, M.E.C., Littman, D.R., Burakoff, S.J., and Robey, E.: The cytoplasmic domain of CD8B regulates lck kinase activation and CD8 T cell development. J. Immunol. 1998; 161:183-191. 3. Jin, Y-J. Friedman, J., and Burakoff, S.J.: Regulation of tyrosine phosporylation in isolated T cell membrane by inhibition of protein tyrosine phosphoases. J. Immunol. 1998; 161:17431750. 4. Chang, J-H. Pratt, J.C., Sawasdikosol, S., Kapeller, R., and Burakoff, S.J.: The small GTP-binding protein Rho potentiates AP-1 transcription in T cells. Mol. Cell. Biol. 1998; 18:4986-4993.

5. Gu, H., Pratt, J.C., Burakoff, S.J., and Neel, B.G.: Cloning and characterization of the major SHP-2 binding protein in hematopoietic cells (p97) reveals a novel pathway for cytokine-induced gene activation. Mol. Cell 1998; 2:729-740. 6. Meng, W., Sawasdikosol, S., Burakoff, S.J., and Eck, M.: Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature 1999; 398:8490. 7. Tang, J., Sawasdikosol, S., Chang, J-H, and Burakoff, S.J.: SLAP, a dimeric adapter protein, plays a functional role in Tcell receptor signaling. Proc. Natl. Acad. Sci. 1999; 96:97759780. 8. Pratt, J.C., van den Brink, M.R.M., Igras, V.E., Walk, S.F., Ravichandran, K.S., and Burakoff, S.J.: Requirement for Shc in T cell antigen receptor-mediated activation of a T cell hybridoma. J. Immunol. 1999; 163:2586-2591. 9. Van den Brink, M.R.M., Moore, E., Horndasch, K.J., Crawford, J.M., Hoffman, J., Murphy, GF and Burakoff, SJ. Fas-deficient lpr mice are more susceptible to graft-versus-host-disease. J. Immunol. 2000;164:469-480. 10. Yu, C-L., Jin, Y-J. and Burakoff, SJ. Cytosolic tyrosine dephosphorylation of STAT5: potential role of SHP-2 in STAT5 regulation. J. Biol. Chem. 2000; 275:599-604. 11. Van den Brink, M.R.M., Moore, E., Ferrara, J.L.M. and Burakoff, S.J.: Graft-versus-host-disease-associated thymic damage results in the appearance of T cell clones with antihost reactivity. Transplant. 2000; 69:446-449. 12. Baksh, S., DeCaprio, J.A. and Burakoff, S.J.: Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kinase 4. Oncogene 2000; 19:2820-2827. 13. Van den Brink MRM, Moore E, Horndasch KJ, Crawford JM, Hoffman J, Murphy GF, Burakoff SJ. Fas ligand-deficient gld

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mice are more susceptible to graft-versus-host disease. Transplantation 2000; 70:184-191. 14. Pratt JC, Igras VE, Maeda H, Baksh S, Gelfand EW, Burakoff SJ, Neel BG, Gu H. Cutting edge: Gab2 mediates an inhibitory phosphatidylinositol 3'-kinase pathway in T cell antigen receptor signaling. J Immunol. 2000 15;165:4158-63. 15. Nishikawa K., Sawasdikosol S., Fruman D. A., Lai J., Songyang Z., Burakoff S.J., Yaffe M.B., Cantley L.C., A peptide library approach identifies a specific inhibitor for the ZAP-70 protein tyrosine kinase. Mol. Cell 2001; 6:969-974. 16. Schmaltz C., Alpdogan O., Horndasch K.J., Muriglan S.J., Kappel B.J., Teshima T., Ferrara J.L.M., Burakoff S.J., van den Brink M.R.M. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cell in graft-versus-leukemia effect. Blood 2001; 97. 2886-2895. 22.Friedman J., Rebel V., Derby R., Bell K., Huang T., Kuypers F., Epstein C., Burakoff S.J., Absence of mitochondrial super oxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant. J. Exp. Med. 2001; 193:925-934. 17. Su M., Yu C-L., Burakoff S.J., Jin YJ, Targeting Src homology 2 domain-containing tyrosine phosphatase (SHP-1) into lipid rafts inhibits CD3--induced T cell activation. J. Immun., 2001; 166:3975-3982. 18. Pedraza-Alva G, Sawasdikosol S, Liu YC, Merida LB, CruzMunoz ME, Oceguera-Yanez F, Burakoff SJ, Rosenstein Y. Regulation of Cbl molecular interactions by the co-receptor molecule CD43 in human T cells. J. Biol. Chem. 2001; 729-37. 19. Mulroy T, McMahon JA, Burakoff SJ, McMahon AP, Sen J. Wnt-1 and Wn-4 regulate thymic cellularity. Eur.J. Immun. 2002; 32:967-71. 20. Baksh S, Widlund H, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, DeCaprio JA, Modiano JF, Burakoff SJ. NFATc2-mediated

repression of cylin-dependent kinase 4 expression. Mol. Cell 2002; 10; 107-081. 21. Sawasdikosol, S., Russo, K. & Burakoff, S.J. (2003). Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2-induced fos gene transcription. Blood 101(9) 3687-3689. PMCID: PMC Journal – In Process. 22. Fragoso R, Ren D, Zhang X, Su M, Burakoff SJ, Jin Y. Lipid raft distribution of CD4 depends on its palmitoylation and association with Lck: Evidence for CD4 induced lipid raft aggregation as an additional mechanism to enhance CD3 signaling. J. Immun., 2003;170: 913-921. 23. Friedman, J., Alpdogan, O., van den Brink, MRM, Liu, C., D. Hurwitz, Boyd, A., Kupper, TS, Burakoff, SJ. Increasing T cell age reduces effector activity but preserves proliferative capacity in a murine allogeneic major histocompatibility complex-mismatched bone marrow transplant model. Biol Blood Marrow Transplant. 2004; 10:448-460. 24. Jin YJ, Zhang X, Boursiquot, JG, Burakoff, SJ. CD4 phosphorylation partially reverses nef down-regulation of CD4. J Immunol. 2004; 173: 495-500. 25. Su MW, Pyarajan S. Chang JH, Yu CL, Jin YJ, Stierhof YD, Walden P, Burakoff SJ. Fratricide of CD8+ cytotoxic T lymphocytes is dependent or cellular activation and perforin-mediated killing. Eur J Immunol. 2004; 2459-70. 26. Friedman JS, Lopez MF, Fleming MD, Rivera A. Martin FM, Welsh ML, Boyd A. Doctrow SR, Burakoff SJ. SOD2deficiency anemia: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness. Blood. 2004; 104: 2565-73. 27. Slavik JM, Lin DG, Burakoff SJ, Hafler DA. Rapamycinresistant proliferation of CD8+ T cells correlates with p27kip1 down-regulation and bcl-xL induction, and is

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prevented by an inhibitor of phosphoinoistide 3-kinase activity. J. Biol Chem. 2004; 279: 910-19. 28. Zambricki E, Shigeoka A, Kishimoto, H, Sprent J, Burakoff S, Carpenter C, Milford E, McKay D. Signaling T cell survival and death by IL-2 and IL-15. Am J Transplant. 2005; 11:262331. 29. Jin JJ, Yi Cai C, Zhang X, Zhang HT, Hirst JA, Burakoff, SJ. HIV Nef-mediated CD4 down-regulation is adaptor protein complex 2 dependent. J. Immun 2005; 022: 3158-3164. 30. Fragoso R, Pyarajan S, Irie HY, Burakoff SJ. CD8/Lck transgene is able to drive thymocyte differentiation. J. Immun. 2006; 6008-15. 31. Sawasdikosol, S., Pyarajan, S., Alzabin, S., Matejovic, G. & Burakoff, S.J. (2007). Prostaglandin E2 activates HPK1 kinase activity via a PKA-dependent pathway. Journal of Biological Chemistry. 282(48) 34693-34699. PMCID: PMC Journal – In Process. 32. Mathews JP, Taylor BS, Bader GD, Pyarajan S, Antoniotti M, Chinnaiyan AM, Sander C, Burakoff SJ, Mishra B. From bytes to bedside: data integration and computational biology for translational cancer research. PLoS Comput Biol. 2007; e12. 33. Pyarajan, S, Matejovic G, Pratt JC, Baksh S, Burakoff SJ. IL-3 Induced C-FOS activation is Modulated by GAB2-Calcineurin Interaction. J. Biol. Chem., 2008; 283:23505-9 34. Jin, Y.J., C. Y. Cai, X. Zhang, H. T. Zhang, and S. J. Burakoff. 2008. Lysine144, a Ubiquitin Attachment Site in HIV-1 Nef, Is Required for Nef-mediated CD4 Downregulation. J Immunol. 2008; 180:7878-86. 35. Alzabin S, Bhardwaj N, Kiefer F, Sawasdikosol S, Burakoff S. Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation. J Immunol. 2009; 182: 6187-94. 36. Alzabin S., Bhardwaj, N., Kiefer, F., Sawasdikosol, S. & Burakoff, S.J. (2009). Hematopoietic progenitor kinase 1 is a

negative regulator of dendritic cell activation. Journal of Immunology. 182(10) 6187-6194. PMCID: PMC Journal – In Process. 37. Alzabin, S., Pyarajan, S., Yee, H., Kiefer, F., Suzuki A., Burakoff, S & Sawasdikosol, S. (2010). Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response. Cancer Immunology, Immunotherapy. 59(3) 419425. PMCID: PMC Journal – In Process. 38. Alzabin S, Pyarajan S, Yee H, Kiefer F, Suzuki A, Burakoff S, Sawasdikosol. Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response. Cancer Immunology and Immunotherapy. 2010 Mar 419-429. 39. Jin YJ, Zhang X, Cai CY, Burakoff SJ. Alkylating HIV-1 Nef - a potential way of HIV intervention. AIDS Res Ther. 2010 Jul 26;7,206. 40. Oh WK, Burakoff SJ. Cancer therapy from bench to bedside. Mt Sinai J Med. 2010 Nov-Dec; 77(6):571-2 .dol: 10. 1002/msj.20221. 41. Cai YC, Zhang X, Sinko, PJ, Burakoff, SJ, Jin, YJ. Two Sorting Motifs, a Ubiquitination Motif, are involved in HIV-1 and Simian Immunodeficiency Virus Nef-Mediated Receptor Endocytosis. J Immunol. 2011 May 15; 186(10:5807-14. Epub 2011 Apr 11. 38. Wang Q, Luan W, Goz V, Burakoff SJ, Hiotis SP. Non-invasive in vivo imaging for liver tumor progression using an orthotopic hepatocellular carcinoma model in immunocometent mice. Liver Int. 2011 Apr 11. Doi: 10.111/j. 1478-3241.2011.02523. 39. Pedrazza-Alva G, Merida LB, Del Rio R, Fierro NA, CruzMunoz ME, Olivares N, Melchy E, Igras V, Hollander GA, Burakoff SJ, Rosenstein Y. CD43 Regulates the Threshold for

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T Cell Activation by Targeting Cbl Functions. IUBMB Life. 2011 Sept 9. Doi: 10.1002/iub.554. 40. Germain RN, Burakoff SJ. A remembrance of Baruj Benacerraf. J Immunol, 2011 Dec1;187(11): 5465-9. 41. Jin YJ, Cai CY, Mezei M, Ohlmeyer M, Sanchez R, Burakoff SJ. Identification of a novel binding site between HIV-1 Nef Cterminal flexible loop and AP2 required for Nef-mediated CD4 downregulation. AIDS Res Hum Retroviruses. 2012 Nov 15. PMID: 23151229.

BIOGRAPHICAL SKETCH NAME Busse, Paula J EDUCATION/TRAINING INSTITUTION AND LOCATION

DEGREE

MM/YY

FIELD OF STUDY

Wellesley College, Wellesley, MA

BA

05/89

Economics

University of Rochester Medical School, Rochester, NY

MD

05/96

Medicine

Mount Sinai School of Medicine, New York City

Certificate

06/03

Clinical Research Training Program (K-30)

A. Personnel Statement My research has focused upon asthma and Hereditary Angioedema (HAE). I have investigated factors, including age, which affects the chronic airway inflammation in asthma. My K08 funding centered upon the role of TNF-a in airway mucus metaplasia in mouse models of asthma. As an internist and a T. Franklin Williams Scholar (program developed by the Association of Specialty Professors for young physicianscientists focusing study on gerontological aspects of their speciality), my research expanded to the study of asthma in older patients. To accomplish this goal, my laboratory developed and characterized a murine model of allergic asthma using aged mice. To expand these studies into human disease, I have evaluated atopic and clinical characteristics in a cohort of older patients with asthma. In addition, I have developed skills and experience in clinical research, in particular for treatment of HAE. I provide care to over 40 patients with HAE and have begun laboratory work to investigate mechanisms by which estrogen may exacerbate HAE.

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POSITION TITLE Associate Professor of Medicine, Division of Clinical Immunology

B. Positions and Honors Professional Positions 1996-1999 Intern and Resident-Internal Medicine, Mount Sinai School of Medicine, New York 1999-2001 Fellowship in Allergy and Immunology, Mount Sinai School of Medicine, New York 2001-2004 Instructor of Medicine, Division of Clinical Immunology-Mount Sinai School of Medicine 2005-2006 Director, Allergy and Asthma Clinic, Mount Sinai Hospital 2004- Assistant Professor of Medicine, Division of Clinical Immunology-Mount Sinai School of Medicine 2006- Assistant Professor of Medicine, Immunology InstituteMount Sinai School of Medicine 2013- Associate Professor of Medicine, Mount Sinai School of Medicine Awards and Other Professional Activities: 1993 Summer Medical Student Intramural Research Fellowship (N.I.H.)

1994 American Academy of Allergy & Immunology Summer Medical Student Fellowship 1999-2002 Accreditation Council for Graduate Medical Education, Residency Review Committee-Allergy and Immunology 2002 ACAAI Young Faculty Award 2003 Dr. Solomon Silver Award in Clinical Medicine (Mount Sinai School of Medicine) 2006- Asthma in Elderly Task Force (AAAAI) 2004-2005 New Allergists/Immunologist Committee Chair (AAAAI) 2007- Association of Speciality Professors (ASP)-Geriatrics Committee (Representative for Allergy and Immunology) 2009- General Clinical Research Center Advisory CommitteeMount Sinai School of Medicine 2006- Annuals of Allergy, Asthma and Immunology (Editorial Board) 2009- Angioedema (Editorial Board) 2010- U.S. Hereditary Angioedema Medical Advisory Board 2013- Protocol Review Group-Clinical Trials Office (Mount Sinai School of Medicine) C. Selected Peer-reviewed Publications (Selected from 29 publications) 1. Birmingham JM, Patil S, Li XM, Busse PJ. The effect of oral tolerance on the allergic airway response in young and aged mice. J Asthma 2013: 50 (2): 122-32. 2. Busse PJ, Cohn RD, Salo PM, Zeldin DL. Characteristics of allergic sensitization among adult asthmatics >55 years: Results from the National Health and Nutrition Examination Survey 2005-2006. Ann Allergy Asthma Immunol 2013; 110 (4) 247-52. 3. Patil SP, Wisnivesky JP, Busse PJ, Halm EA, Li XM. Detection of immunological biomarkers correlated with asthma

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4. 5. 6.

7.

8.

9.

10.

control and quality of life measurements in sera from chronic asthmatic patients. Ann Allergy Asthma Immunol 2011; 106 (3): 205-13. Busse PJ, Mathur SK. Age-related changes in immune function: Impact on airway inflammation. J Allergy Clin Immunol; 2010; 126 (4): 690-9. Busse PJ, Lurshurchadia L, Sampson H, Halm EA, Wisnivesky J. Allergic sensitization among inner-city elderly patients with persistent asthma. J. Asthma 2010; 47 (7): 781-5. Zuraw BL, Busse PJ, White M, et al. Safety and Efficacy of Nanofiltered C1 Inhibitor Concentrate For Acute And Prophylactic Treatment Of Hereditary Angioedema Due to C1 Inhibitor Deficiency. N Engl J Med 2010: 24(7): 1047-55 Busse PJ, Kiran Kilaru, Teng Fei Zhang, Brian Schofield, Sangita Patil, Xiu-Min Li. Treatment with Traditional Chinese Herbal Formula, ASHMI, suppresses features of allergic asthma in antigen sensitized and challenged aged mice. Ann Allergy Asthma Immunol 2010; 104 (3): 236-246. Song Y, Qu C, Srivastava K, Yang N, Busse PJ, Zhao W, Li XM. Food Allergy Herbal Formula -2 (FAHF-2) protection against peanut anaphylactic reaction is via inhibition of mast cells and basophils. J Allergy Clin Immunol 2010; 126: 1208-17. Busse PJ, Kiran Kilaru, Teng Fei Zhang, Brian Schofield, Sangita Patil, Xiu-Min Li. Treatment with anti-Tumor Necrosis Factor alpha decreases airway mucus gene expression in a murine model of allergic asthma. Ann Allergy Asthma Immunol 2009; 103 (4): 295-303. Kelly-Pieper K, Patil SP, Busse PJ, Yang N, Sampson H, Wisnivesky J, Li X-M, Kattan M. Safety and tolerability of an antiasthma herbal formula (ASHMITM) in adult asthmatics: a randomized, double-blinded, placebo-controlled, dose escalation phase I study. J of Alternative and Complementary Medicine 2009; 15: 735-43.

11. Busse PJ, Kilaru K. Complexities of Diagnosis and Treatment of Allergic Respiratory Disease in the Elderly. Drugs Aging 2009; 26 (1): 1-22. 12. Busse PJ, Zhang, TF, Srivastava K, Schofield B, Li XM. Effect of ageing on pulmonary inflammation, airway hyperresponsiveness and T and B cell responses in antigen sensitized and challenged mice. Clin Exp Allergy 2007; 37: 1392-1403. 13. Busse PJ, Zhang TF, Srivastava K, Sealfon S, Lin B, Li XM. Chronic administration of tumor necrosis factor alpha increases airway mucus gene expression in vivo. J Allergy Clin Immunol 2005; 116: 1265-63. 14. Busse PJ, Wang J, Halm EA. Underuse of Allergen Sensitization Evaluation and Trigger Avoidance Education among Inner-city Adults with Persistent Asthma. J Allergy Clin Immunol 2005; 116: 146-152. 15. Busse PJ, Noone S, Nowak A, Sicherer S, Sampson HA. Recurrence of Peanut Allergy. N Engl J Med 2002; 347: 15351536.

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BIOGRAPHICAL SKETCH NAME Cerutti, Andrea EDUCATION/TRAINING INSTITUTION AND LOCATION Padua University School of Medicine, Italy Padua University School of Medicine, Italy A. Positions and Honors Positions and Employement 2010- Professor, Immunology Institute, Department of Medicine, Division of Clinical Immunology, Mount Sinai School of Medicine, New York, NY 2009- ICREA Research Professor, Catalan Institute for Research and Advanced Studies, IMIM-Hospital del Mar, PRBB, Barcelona, Spain 2008 Tenure, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 2006-2009 Associate Professor, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 2000-2006 Assistant Professor, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 1999-2000 Visiting Assistant Professor, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 1996-1998 Senior Research Associate, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 1993-1994 Attending Physician (Medical Officer), Padua Type-A Military Hospital, Padua, Italy 1990-1995 Residency, Department of Clinical and Experimental Medicine, Padua University School of Medicine, Padua, Italy 108

POSITION TITLE Professor DEGREE M.D. Board

MM/YY 1990 1997

FIELD OF STUDY Medicine Hematology

Other Experience and Professional Memberships 2010- Associate Editor, Mucosal Immunology 2008- Section Editor, The Journal of Immunology 2008- Member, Society for Mucosal Immunology 2004-2008 Associate Editor, The Journal of Immunology 2000- Reviewer (articles), Science, Nature, Nature Immunology, Nature Medicine, Nature Biotechnology, Immunity, Blood, The Journal of Experimental Medicine, The Journal of Clinical Investigation, The Journal of Immunology, European Journal of Immunology, Proceedings of the National Academy of Sciences, Mucosal Immunology, International Immunology, The Journal of Leukocyte Biology, Arthritis and Rheumatism, Rheumatology, Gastroenterology, PLoS Pathogens, PLoS ONE, Retrovirology, Gut, The FASEB Journal, The Journal of Cell Biology, The Journal of Cell Physiology, American Journal of Pathology, The Journal of Rheumatology, British Journal of Cancer. 2000- Reviewer (grants), National Institutes of Health (NIAID, NIAMS), European Research Council (ERC), Italian Association for Cancer Research (AIRC), The Wellcome Trust, Dutch Cancer Society, US-Israel Binational Science Foundation, Kentucky Science and Engineering Foundation, Sanquin Institute. 1999- Member, The American Society of Hematologists 1998- Member, The American Association of Immunologists Honors and Awards 2012 Member, The New York Academy of Sciences 2009 Member, The American Society for Clinical Investigation

2007 Recipient, The Irma T. Irschl Career Scientist Award 2006 Member, The Henry Kunkel Society 2006 Recipient, Award for Excellence in Mentoring, Weill Medical College Postdoctoral Association 2001 Recipient, Travel Award, The American Association of Immunologists 1999 Recipient, Career Development Award, The S.L.E. Foundation 1998 Recipient, Lorenza Ceschiatti Prize for Research in Oncology C. Publications (15 from a total of 90) 1. Magri G, Miyajima M, Bascones S, Puga I, Cassis L, Barra CM, Comerma L, Gentile M, Cols M, Serrano S, Aróstegui JI, Juan M, Yagüe J, Fagarasan S, Cerutti A. Splenic innate lymphoid cells enhance front-line antibody responses by linking marginal zone B cells with neutrophils Nature Immunol. 2014, 15:354-364. 2. Shan M, Gentile M, Yeiser JR, Walland AC, Borstein VU, Chen K, He B, Cassis L, Bigas A, Cols M, Comerma L, Huang BH, Blander JM, Xiong HB, Mayer L, Berin C, Augenlicht LH, Velcich A, Cerutti A. Mucus enhances gut homeostasis and oral tolerance by delivering tolerogenic signals. Science 2013, 342:447-453. 3. Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innatelike antibody-producing lymphocytes. Nature Rev. Immunol. 2013 13:118-132. 4. Puga I, Cols M, Barra C, He B, Cassis L, Gentile M, Comerma L, Chorny A, Shan S, Xu W, Magri G, Knowles DM, Tam W, Chiu A, Bussel JB, Serrano S, Lorente JA, Bellosillo B, Lloreta J, Juanpere N, Alameda F, Díaz de Heredia C, Torán N, Català A, Torrebadell M, Fortuny C, Cusi V, Carreras C, Diaz G, Blander JM, Farber CM, Silvestri G, Cunningham-Rundles C, Dufour C, Notarangelo L, Lougaris V, Plebani A, Casanova JL, Aróstegui JI, Juan M, Yagüe J, Mahlaoui N, Donadieu J, Chen K, Cerutti A. B cell-helper neutrophils induce immunoglobulin diversification and production in the marginal zone of the spleen. Nature Immunol. 2011, 13:170-180.

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5. Cerutti A, Chorny A, Chen K. Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 2011, 29:273-293. 6. Cerutti A, Chen K. Vaccination strategies to promote mucosal antibody responses. Immunity 2010, 33:479-491. 7. He B, Santamaria R, Xu W, Cols M, Chen K, Puga I, Shan MM, Xiong H, Bussel J B, Chiu A, Puel A, Reichenbach J, Laszlo M, Doffinger R, Vasconcelos J, Issekutz A, Krause J, Davies G, Li X, Grimbacher B, Plebani A, Meffre E, Picard C, Cunningham-Rundles C, Casanova J-L, Cerutti A. TACI triggers immunoglobulin class switching by activating B cells through the adaptor protein MyD88. Nature Immunol. 2010, 11:236-245. 8. Xu W, Santini PA, Sullivan JS, He B, Shan M, Ball SC, Dyer DW, Chadburn A, Knowles DM, Chiu A, Chen K, Cerutti A. HIV-1 evades virus-specific IgG2 and IgA class switching by targeting systemic and intestinal B cells via long-range intercellular conduits. Nature Immunol. 2009, 10:1008-1017. 9. Chen K, Xu W, Wilson M, He B, Miller BH, Bengten E, Edholm ES, Santini PA, Rath P, Chiu A, Cattalini M., Litzman J, Bussel J, Huang B, Riesbeck K, Cunningham-Rundles C, Plebani A, Cerutti A. Immunoglobulin D enhances immune surveillance by activating antimicrobial, inflammatory and B cell-stimulating programs in basophils. Nature Immunol. 2009, 10:889-898. 10. Cerutti A. The regulation of IgA class switching. Nature Rev. Immunol. 2008, 8:421-434. 11. Cerutti A and Rescigno M. The biology of intestinal IgA responses. Immunity 2008, 28:740-750. 12. He B, Xu W, Santini P, Polydorides A, Chiu A, Estrella J, Shan M, Chadburn A, Villanacci V, Plebani A, Knowles DM, Rescigno M, Cerutti A. Intestinal bacteria induce T cell-independent immunoglobulin A2 class switching by triggering epithelial-cell secretion of the cytokine APRIL. Immunity 2007, 26:812-826. 13. Xu W, Santini P, Chiu A, Shan S, Chadburn A, Knowles DM, He B, Cerutti A. Epithelial cells trigger frontline immunoglobulin class

switching through a pathway regulated by the inhibitor SLPI. Nature Immunol. 2007, 8:294-303. 14. Qiao X, He B, Chiu A, Knowles MD, Chadburn A, Cerutti A. Human immunodeficiency virus Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nature Immunol. 2006, 7:302-310.  

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15. Litinskiy BM, Nardelli B, Hilbert D, He B, Schaffer A, Casali P, Cerutti A. Dendritic cells induce CD40-independent immunoglobulin class switching by stimulating B cells through BLyS and APRIL. Nature Immunol. 2002, 3:822-829.

BIOGRAPHICAL SKETCH NAME Chen, Benjamin K. EDUCATION/TRAINING INSTITUTION AND LOCATION Stanford University, Stanford, CA Rockefeller University, New York, NY Mentor: David Baltimore Weill College of Medicine of Cornell, New York, NY Whitehead Institute for Biomedical Research, Cambridge, MA Mentor: Peter S. Kim A. Personal Statement Dr. Chen’s research career has focused on HIV-host cell interactions that support viral replication. The work from his laboratory has focused on how the assembly and production of HIV in T cells is regulated by the cell-cell contacts and how these contacts called virological synapses (VS) enhance infection. The laboratory has designed recombinant forms of infectious HIV that facilitate measurement of the steps of the virus life cycle. Utilizing fluorescently tagged HIV clones and live microscopy his laboratory revealed that cell adhesion induced by the viral Env protein induces the active recruitment of assembling virus particles to the cell-cell junction. With live 3dimensional confocal microscopy methods, the laboratory was the first to capture the dynamic directional movement of the viral structural protein Gag into the VS. This work revealed a novel endocytic entry pathway that is mediated by the VS. The laboratory has discovered that cell-mediated HIV infection is a more efficient mode of infection, resistant to patient neutralizing antibodies, and the predominant mode of infection   111

POSITION TITLE Associate Professor DEGREE B.A.S.

MM/YY 06/90

FIELD OF STUDY Biology & Philosophy

Ph.D.

05/98

Molecular Virology

M.D.

05/99

Medicine

Post doc

Biochemistry/Virology

in vitro. We have found that infection through the VS can result in the simultaneous transmission of multiple genetic copies of HIV, making HIV functionally multiploid. This mode of inheritance may explain the ability of HIV to tolerate high levels of genetic diversity. Recent work also suggests that the regulation of Env fusogenicity during infection through the VS mediates resistance of VS to neutralizing antibodies. Thus the VS may be an important vaccine target in the future. In addition to studying the mechanisms of the synapse formation, current studies in the laboratory have also focused on the role of cellto-cell infection in a parenteral model of HIV transmission in humanized mice. The goal of these studies is to visualize VS in vivo and to characterize how they participate in viral spread in vivo. Overall, the studies on VS examine how immune cells actively participate in HIV dissemination providing a new paradigm with which to understand many aspects of HIV pathogenesis. B. Positions and Honors Research Experience/Employment:

2010-present Mount Sinai School of Medicine, New York, NY Associate Professor, Division of Infectious Disease, Department of Medicine Associate Professor, Immunology Institute Associate Professor, Department of Microbiology Associate Professor, Department of Pharmacology and Systems Therapeutics 2003-2009 Mount Sinai School of Medicine, New York, NY Assistant Professor, Department of Pharmacology and Systems Therapeutics; Immunology Institute Division of Infectious Disease, Department of Medicine 1999-2003 Whitehead Institute for Biomedical Research, M.I.T., Cambridge, MA Postdoctoral fellow, Advisor: Dr. Peter S. Kim 1992-1997 Rockefeller University, New York, NY Doctoral student in molecular virology, Advisor: Dr. David Baltimore 1994-1997 Massachusetts Institute of Technology, Department of Biology, Cambridge, MA Research affiliate during doctoral studies, Advisor: Dr. David Baltimore 1992-1994 Aaron Diamond AIDS Research Center, New York University, New York, NY Research affiliate during doctoral studies, Advisors: Dr. David Ho and Dr. Nathaniel Landau 1988-1990 Stanford University, Department of Biology, Stanford, CA Undergraduate research assistant in virology, Advisor: Dr. Edward Mocarski Honors fellowships: 2009 Avant Garde Award in HIV/AIDS research, National Institute of Drug Abuse, NIH

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2007 Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases 2007 Irma T. Hirschl Monique Weill-Caulier Career Scientist Award 2000-2003 National Research Service Award, National Institute for Allergy and Infectious Disease, National Institutes of Health 1990 Graduation with Honors in Biological Sciences, Stanford University 1990 Graduation with Distinction in Philosophy, Stanford University Professional Societies: 2000-present American Society for Microbiology 1991-present Association for the Advancement of Science 2010-present American Society for Clinical Investigation Professional Service: Consulting editor: Journal of Clinical Investigation Grant Review: ad hoc NIH AIDS fellowship study section, NIH/NIAID special emphasis review panel, Wellcome Trust Foundation Ad Hoc Reviewer: Journal of Virology, Plos Pathogen, Journal of Experimental Medicine, PNAS, JASN, Virology, Vaccine, Viruses, Current Topics in Microbiology C. Selected Peer Reviewed Publications: 1. Amanda M. Micsenyi, Chati Zony, Raymond A. Alvarez, Natasha D. Durham, Benjamin K. Chen*, and Mary E. Klotman*. Post-integration HIV-1 infection of cervical epithelial cells mediates contact-dependent productive infection of T cells. Journal of Infectious Diseases. 208(11):1756-67, 2013. *Co-corresponding authors. 2. Benjamin M. Dale, Raymond A. Alvarez, and Benjamin K. Chen. Mechanisms of enhanced HIV spread through T-cell

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virological synapses. Immunological Reviews. 251(1):113-24. 2013. PMID: 23278744 [PubMed - in process] Benjamin K. Chen, T cell virological synapses and HIV-1 pathogenesis. Immunogical Research. 251(1):113-24. 2012. PMID: 23278744 [PubMed - in process] Natasha D. Durham, Alice W. Yewdall, Ping Chen, Rebecca Lee, Chati Zony, James E. Robinson, and Benjamin K. Chen, Neutralization resistance of HIV-1 virological synapsemediated infection is regulated by the gp41 cytoplasmic tail. Journal of Virology. 86(14):7484-95. 2012. Cristina Maria Costantino, Achla Gupta, Alice W. Yewdall, Benjamin M. Dale, Lakshmi A. Devi*, and Benjamin K. Chen* (* co-corresponding authors). Cannabinoid receptor 2mediated attenuation of CXCR4-tropic HIV infection in primary CD4+ T cells. Plos One 7(3):e33961. 2012. Benjamin M. Dale, Gregory P. McNerney, Deanna L. Thompson, Wolfgang Hubner, Kevin de los Reyes, Frank Y. S. Chuang, Thomas Huser,and Benjamin K. Chen. Endosomal HIV-1 particle maturation activates viral membrane fusion following transfer across virological synapses. Cell Host & Microbe. 10(6):551-62. 2011. Armando Del Portillo, Joseph Tripodi, Vesna Najfeld, Dominik Wodarz, David N. Levy, and Benjamin K. Chen BK. Multiploid inheritance of HIV-1 during cell-to-cell infection. Journal of Virology. Vol 85(14): 7169-76. 2011. Ping Chen, Benjamin K. Chen*, Arevik Mosoian, Thomas Hays, Michael J. Ross, Paul E. Klotman and Mary E. Klotman. Lymphocyte-to-epithelial cell HIV transfer induces viral gene expression in renal tubular epithelial cells. Journal of the American Society of Nephrology. 22(3):496-507. 2011. *Corresponding author Ana C. Tuyama, Feng Hong, Yedidya Saiman, Chuansheng Wang, Derya Ozkok, Arevik Mosoian, Ping Chen, Benjamin K.

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Chen, Mary E. Klotman, and Meena B. Bansal. Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis. Hepatology. 52(2):612-22. 2010. Benjamin M. Dale B, Gregory P. McNerney, Deanna L. Thompson, Wolfgang Hübner, Thomas Huser, Benjamin K. Chen. Visualizing cell-to-cell transfer of HIV using fluorescent clones of HIV and live confocal microscopy. Journal of Visualized Experiments. Vol 44 Oct 7;2010. Benjamin M. Dale, Gregory P. McNerney, Wolfgang Hübner, Thomas R. Huser and Benjamin K. Chen. Tracking and quantitation of fluorescent HIV during cell-to-cell transmission. Methods. 53(1):20-6. 2010. Gregory P. McNerney, Wolfgang Hübner, Benjamin K. Chen, Thomas Huser. Manipulating CD4(+) T cells by optical tweezers for the initiation of cell-cell transfer of HIV-1. J Biophotonics. 3(4):216-223. 2010. Wolfgang Hübner, Gregory P. McNerney, Benjamin M. Dale, Ping Chen, Ronald E. Gordon, Frank Y. S. Chuang, Xiao-Dong Li, David M. Asmuth, Thomas Huser, and Benjamin K. Chen. Quantitative 3D Video Microscopy of HIV Transfer Across T cell Virological Synapses. Science. 323(5922):1743-7. (2009) Wolfgang Hübner, Ping Chen, Armando Delportillo, Yuxin Liu, Ronald Gordon and Benjamin K. Chen. Sequence of HIV1 Gag localization and oligomerization monitored with continuous, live confocal imaging of a replicationcompetent, fluorescently tagged HIV-1. Journal of Virology, 81(22):12596-607. 2007. Ping Chen, Wolfgang Hübner, Matthew Spinelli, and Benjamin K. Chen. Predominant mode of HIV transfer between T cells is mediated by sustained Env-dependent

neutralization-resistant virological synapses. Journal of Virology, 81(22):12582-95. 2007. 16. Ping Chen, Kareen Riviere, Wolfgang Hübner, Yu-Xin Liu and Benjamin K. Chen. Chimeric HIV-1 containing SIV matrix exhibit enhanced assembly in murine cells and replicate in a cell type dependent manner in human T cells. Virology 349(1):1-12. 2006. 17. Benjamin K. Chen, Itay Rousso, Sung Shim, Peter S. Kim. Efficient assembly of an HIV/MLV Gag-chimeric virus in murine cells. Proceedings of the National Academy of Sciences, U S A. 98(26): 15239-15244. 2001. 18. Itay Rousso, Mark B. Mixon, Benjamin K. Chen, Peter S. Kim. Palmitoylation of the HIV-1 envelope glycoprotein is critical for viral infectivity. Proceedings of the National Academy of Sciences, U S A. 97(25):13523-13525. 2000. 19. Shigemi Kinoshita, Benjamin K. Chen, Hideto Kaneshima, and Garry P. Nolan. Host control of HIV-1 parisitism in T cells by the nuclear factor of activated T cells. Cell. 95(5):595-604. 1998. 20. Rajesh T. Gandhi, Benjamin K. Chen, and David Baltimore. Human immunodeficiency virus type 1 directly kills T cells by a Fas-independent mechanism. Journal of Experimental Medicine. 187(7):1113-1122. 1998. 21. Kathleen L. Collins, Benjamin K. Chen, Spyros A. Kalams, Bruce D. Walker, and David Baltimore. HIV-1 Nef protein protects infected primary human cells from killing by cytotoxic T lymphocytes. Nature. 391(6665): 397-401. 1998. [PMID: 9450757]

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BIOGRAPHICAL SKETCH NAME Chen, Shu-Hsia EDUCATION/TRAINING INSTITUTION AND LOCATION Shoo-Chow Univ., Taiwan, ROC Nat’l Yang-Ming University, Taiwan, ROC Nat’l Yang-Ming University, Taiwan, ROC A. Personal Statement My lab is interesting on the mechanism of myeloid derived suppressor cells (MDSC) and T regulatory cells (Treg) mediated immune suppression in tumor microenvironment, and the control of myeloid cells differentiation into to M1 vs. M2 macrophage, which may facilitate the intervention of cancer immune therapy and control tumor inflammation and metastases. I have the expertise and motivation that are necessary to serve as a mentor for this grant application. I have a broad background in cancer biology, immune therapy, and immune tolerance, with specific expertise in the area of MDSC-mediated immune suppression, Treg regulation and macrophage differentiation. As a senior immunology faculty member at Mount Sinai School of Medicine, New York, I carried out several pioneer studies in immune modulatory therapy and the mechanisms behind immune suppression mediated by myeloidderived suppressor cells (MDSC) and their multiple suppressive functions in the regulation of host immunity. I have broadspectrum knowledge on the topic of MDSCs enabling me to provide the proper intellectual guidance to ensure the trainees’ success in their project and help them establish their independence. I have trained more than 20 research fellows and students, and currently have over 12 former fellows, which have 115

POSITION TITLE Professor DEGREE B.S. M.S. Ph.D.

MM/YY 07/85 07/87 07/92

FIELD OF STUDY Microbiology Microbiol. and Immunol. Microbiol. and Immunol.

gone on to become faculty and conduct their own independent research internationally. In addition, I have considerable experience in conducting clinical translational work and moving basic research to clinical application. I have been continuously supported by multiple NIH funded research grants in both preclinical basic researches and clinical trials. I also served as a regular NIH reviewer on the panel for the TTT (transplantation, tolerance, tumor immunology) study section, which is indicative of my scientific training and expertise in immune modulation therapy in cancer and immune tolerance area. I will utilize my expertise, training experience, and leadership to assist in the success of these trainees. In summary, I have demonstrated my track record of training multiple students and fellows in becoming independent investigators, have successful and productive research and my expertise and experience qualify me as the mentor for this application. B. Positions and Honors Positions and Employment 1992-1995 Research Associate, Howard Hughes Medical Institute/Department of Cell Biology, Baylor College of Medicine, Houston, Texas 1995-1996 Assistant Professor, Department of Cell Biology, Baylor College of Medicine, Houston, Texas

1997-2004 Assistant Professor, Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 2005-2010 Associate Professor, Dep. Gene and Cell Medicine, Dep. of Oncological Science, Dep. General Surgery, Mount Sinai School of Medicine, New York, New York 2010-present Professor, Dep. Oncological Sciences, Dep Surgery, Mount Sinai School of Medicine, New York, NY Other Experience and Professional Memberships 1995Active Member, American Association for Cancer Research 1995- Active Member, American Association of Immunologist 1999, 2001 Grant reviewer for RAID program, NCI. 2003 Grant reviewer in Experimental Immunology study section, NIH. 2005 Ad Hoc member for Center for Scientific Reviewer in Transplantation, Tolerance and Tumor Immunology (TTT) study section, NCI, NIH. 2005 Ad Hoc member in Center for Scientific Review for Special Emphasis Panel, NIH. 2005 Ad Hoc member in Clinical Research Review Committee for National Center for Research Resources (NCRR), NIH. 2007 Scientific Reviewer for Department of Defense (CDMRP), Prostate Cancer Research Program 2008 Scientific Reviewer for Department of Defense (CDMRP), Breast Cancer Research Program. 2009 Scientific Reviewer, Department of Defense (CDMRP), Prostate Cancer Research Program (PCRP), the Idea Development Award (IDA) and Synergistic Idea Development Award (SIDA). 2006-2009 Regular Member in Center for Scientific Review of Transplantation, Tolerance and Tumor immunology (TTT) study section, NIH.

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2010 University of Pittsburgh Cancer Institute and NIH designated Cancer Center site visit. Primary reviewer for Cancer Immunology Program and share resource on immunological monitoring and cellular products laboratory, NCI, NIH 2011, 12 Regular member for NIH (III) special emphasized Panel and Ad Hoc TTT study section 2012-present Visiting professor National Health Research Institute (NHRI), Taiwan, ROC 2013-present Advisory board member of the Emerging and Reemerging Infectious Disease (EID) program of National Science Council, Taiwan Honors 1990 The award of outstanding research of hepatitis and hepatoma in the 3rd annual Society of Chinese Bioscientist Association Meeting (SCBA), Hong Kong. 1991 Selected presenter and travel award (offered by Ministry of Education R.O.C.) to attend the international meeting on Molecular Biology of Hepatitis B Virus, Paris, France. 1992 Outstanding Research award, Dr. Ming-Lin Wang Biomedical Research Foundation, Taipei, Taiwan. 1995 Selected presenter and travel award (offered by BristolMyers Oncology Division) to attend 1995 American Association for Cancer Research (AACR) Meeting, Toronto. 1996 Texas higher educational award. 1996-1998 $70,000/year. 2002 AACR annual meeting at San Francisco, Experimental Therapy Section Chair. 2006-2008 Black Family Stem Cell Foundation exploratory award. 2010 Tisch Cancer Institute, Developmental fund award.

2012 The Center for Therapeutic Antibody Discovery (CTAD) obtains the Award form Institute for Translational Sciences and the Office of Technology and Business Development, MSSM. 2010-2014 Journal of Immunology, Associate Editor. C. Selected Peer-reviewed Publications Most relevant to the current application 1. Ping-Ying Pan, George X. Wang, Bingjiao Yin, Junko Ozao, Teresa Ku, Celia M. Divino and Shu-Hsia Chen (2008) Reversion of immune tolerance by modulation of myeloid derived suppressor cell development in advanced malignancy. Blood 111:219-228. 2. Ping-Ying Pan*, Junko Ozao, Zuping Zhou, Shu-Hsia Chen (2008) Advancements in Immune Tolerance at Theme Issue on Cell-based Therapeutics. Advanced Drug Delivery Reviews. 60:91-105. 3. Yongpeng Gu, J. Yang, W. Liu, H. Li, J. Bromberg, Shu-Hsia Chen, Lloyd Mayer, Jay Unkless, Huabao Xing (2008) Interleukin-10 (IL-10) suppress Th17 cytokine in macrophage and T cells. European J. of Immunology Jul;38(7):1807-13. 4. Junko Ozao, Ge Ma, Johnny Kao, Celia Divino, Max Sung, Myron Schwartz, Ping-Ying Pan, Shu-Hsia Chen (2009) Novel target of tyrosine kinase inhibitor reverses immune tolerance for immune therapy in hepatic colon carcinoma model, Cancer Research, 69(6):2514-22. 5. Ping-Ying Pan, Kare Webber, George Wang, Junko Ozao, Celia Divino, Shu-Hsia Chen (2010) Cancer Res. 1;70(1):99-108. PMID: 19996287 6. Zhou Z, French DL, Ma G, Eisenstein S, Chen Y, Divino CM, Keller G, Chen SH*, Pan PY. (2010) Development and Function of Myeloid-Derived Suppressor Cells Generated from Mouse Embryonic and Hematopoietic Stem Cells. Stem Cells. Jan 13. [Epub ahead of print]

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7. Peter Boros, Jordi C. Ochando, Shu-Hsia Chen, Jonathan S. Bromberg 2010 Myeloid-derived suppressor cells: natural regulators for tolerance Human Immunology. Nov;71(11):1061-6. PMID: 20705113,PMC28101198. 8. Bingjiao Yi, George Wang, Junko Ozao, Celia Divino, Johnason Bromberg, Shu-Hsia Chen and Ping-Ying Pan 2010 Myeloid Derived Suppressor Cell-Mediated Immune Suppression to prevent the diabetic autoimmune response. J. Immunology. 2010 Nov 15;185(10):5828-34. PMID: 20956337,PMC2826879. 9. Meseck M, Huang T, Ma G, Wang G, Chen SH*, Woo SL*. 2011 A functional recombinant human 4-1BB ligand for immune costimulatory therapy of cancer. J Immunother. Mar;34(2):175-82. PMID:21304403 PMCID: PMC3066178. 10. Ge Ma, Ping-Ying Pan, Samuel Eisenstein, Celia M Divino, Clifford A. Lowell, Toshiyuki Takai and Shu-Hsia Chen, 2011 Paired Immunoglobin Like Receptor-B regulates the suppressive function and fate of myeloid derived suppressor cells. Immunity, Mar 25;34(3):385-95. (Cover future for that issue) PMID:21376641 PMCID: PMC3064726. 11. Peng S, Ma B, Chen SH, Hung CF, Wu T. DNA vaccines delivered by human papillomavirus pseudovirions as a promising approach for generating antigen-specific CD8+ T cell immunity. Cell Biosci. 2011 Jul 28;1:26. 12. Gobind Singh, Daigo Hashimoto, Xiaocai Yan, Julie Helft, Ge Ma, Rui F Qiao, Colin R Kennedy, Shu-Hsia Chen, Miriam Merad, and Andrew M Chan, 2012, R-Ras is required for murine dendritic cell maturation and CD4+ T-cell activation, Blood. 2012 Feb 16;119(7):1693-701. Epub 2011 Dec 14. PMID: 22174156, PMCID: PMC3286347 13. Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G, Cannan D, Ramacher M, Kato M, Overwijk WW, Chen SH, Umansky VY, Sikora AG. Tumor-Expressed Inducible Nitric Oxide Synthase Controls Induction of

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Functional Myeloid-Derived Suppressor Cells through Modulation of Vascular Endothelial Growth Factor Release. J Immunol. 2012 Jun 1;188(11):5365-76. Epub 2012 Apr 23. PMID: 22529296 , PMCID: PMC3358566 Ochando JC, Chen SH. Myeloid-derived suppressor cells in transplantation and cancer. Immunol Res. 2012 Apr 26. PMID: 22535241 Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, Hyunh H, Kang X, Silvany R, Wan X, Ye J, Cantó AP, Chen SH, Wang HY, Ward ES, Zhang CC. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature. 2012 May 30;485(7400):656-60. PMID: 22660330 PMCID: PMC3367397 Fu S, Yang Y, Tirtha D, Yen Y, Zhou BS, Zhou MM, Ohlmeyer M, Ko EC, Cagan R, Rosenstein BS, Chen SH, Kao J. γ-H2AX Kinetics as a Novel Approach to High Content Screening for Small Molecule Radiosensitizers. PLoS One. 2012;7(6):e38465. Epub 2012 Jun 29. PMID: 22768044 Tong CC, Ko EC, Sung MW, Cesaretti JA, Stock RG, Packer SH, Forsythe K, Genden EM, Schwartz M, Lau KH, Galsky M, Ozao-Choy J, Chen SH, Kao J. Phase II Trial of Concurrent Sunitinib and Image-Guided Radiotherapy for Oligometastases. PLoS One. 2012;7(6):e36979. Epub 2012 Jun 27. PMID: 22761653 Wen-Chin Yang, Ge Ma, Shu-Hsia Chen, and Ping-Ying Pan, Polarization and Reprogramming of myeloid-derived suppressor cells: mechanism, function and therapy, JMCB, 2013 Accepted. Samuel Eisenstein, Brian A. Coakley, Karen Briley-Saebo, Ge Ma, Marcia Meseck, Stephen Ward, Celia Divino, Savio Woo, Shu-Hsia Chen, Ping-Ying Pan. A novel role of myeloid derived suppressor cells for tumor-specific therapeutic targeting Cancer Research, 2013 accepted.

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BIOGRAPHICAL SKETCH NAME Cho, Judy H. EDUCATION/TRAINING INSTITUTION AND LOCATION Ohio State University, Columbus, OH Ohio State University, Columbus, OH Northwestern University, Chicago, IL Northwestern University, Chicago, IL University of Chicago, Chicago, IL A. Personal Statement Dr. Cho has extensive experience in defining genetic factors underlying susceptibility to inflammatory bowel disease (IBD). She was the senior investigator reporting the initial associations of NOD2 to Crohn’s disease, the IBD GWAS first identifying the interleukin 23 receptor associations, and most recently, the IBD Immunochip manuscript. For the past eleven years, she has served as chair of the steering committee and Principal Investigator of the 7 center NIDDK IBD Genetics Consortium. She is particularly interested in defining the genetic architecture underlying the higher IBD prevalence among Ashkenazi Jews. Her laboratory is also interested in defining the genetic architecture underlying differentiation of distinct immune cell subsets, inter-individual differences of which underlie susceptibility and resistance to mycobacterial infection and Crohn’s disease. At Mount Sinai, she serves as Director for Clinical and Translational Education (CePORTED). B. Positions and Honors Positions and Employment 1990-1991 Instructor of Clinical Medicine, Northwestern   119

POSITION TITLE Ward-Coleman Professor, Vice-Chair Gastroenterology and Genetics & Genomics DEGREE B. A. M.D. Post-doctoral training Post-doctoral training Post-doctoral training

MM/YY 1979-1982 1982-1986 1987-1990 1990-1991 1991-1995

FIELD OF STUDY Biochemistry Medicine Internal Medicine Chief Resident Gastroenterology

University 1995-1997 Instructor of Medicine, University of Chicago Hospitals 1998-2004 Assistant Professor of Medicine, University of Chicago Hospitals 2001-2006 Committee on Genetics, University of Chicago 2004-2006 Associate Professor of Medicine, University of Chicago Hospitals 2006-present Associate Professor of Medicine and Genetics, Yale University Director, IBD Center, Yale University 2012-2013 Henry J. and Joan W. Binder Professor of Medicine and Genetics, Yale University 2013- Ward-Coleman Professor, Vice-Chair of Genetics & Genomics and Gastroenterology, Icahn School of Medicine at Mount Sinai in New York Honors 1982 Summa cum laude, Ohio State University, Biochemistry 1981 Member, Phi Beta Kappa 1990 Member, Alpha Omega Alpha

1990-1991 Chief Medical Resident, Northwestern University 1990 Medical Student Teaching Award, Northwestern University 2004-2008 Member, Genetics of Health and Disease study section 2005 Member, American Society of Clinical Investigation 2005 2007-2011 Editorial Board, American Journal of Human Genetics 2007-2011 Editorial Board, Clinical and Translational Sciences 2007- Editorial Board, Human Molecular Genetics 2008-2011 Member, American Society of Clinical Investigation Council 2008-2011 2010 NIH Wednesday Afternoon Lecture seminar 2011-2015 NIDDK Advisory Council 2012-2015 Member, Research Policy Committee, American Gastroenterological Association C. Selected Peer-reviewed Publications (From over 90 peer-reviewed publications) 1. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitjovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan A, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Buning C, Cohain A, Cichon S, D’Amato M, De Jong DJ, Devaney KL, Dubinsky M, Edwards C, Ellinghous D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK,

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Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson CK, Zhao H, The International IBD Genetics Consortium, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119-124. PMCID: PMC3491803 Huber S, Gagliani N, Zenewicz LA, Huber FJ, Hedl M, Zhang W, O’Connor W, Murphy AJ, Valenzuela DM, Yancopoulos GD, Booth CJ, Cho JH, Ouyang W, Abraham C, Flavell RA. The IL-22—IL-22BP axis is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 2012; 491: 259-63. PMCID: PMC3493690 Zhang W, Ferguson J, Ng SM, Goh G, Lin A, Esplugues E, Flavell RA, Abraham C, Zhao H, Cho JH. Effector CD4+ T cell expression signatures and immune-mediated disease associated genes. Plos One 2012; 7: e38510. PMCID: PMC3371029 Zhang W, Hui K, Gusev A, Warner N, Ng SME, Ferguson J, Choi M, Burberry A, Abraham C, Mayer L, Desnick RJ, Cardinale CJ, Hakonarson H, Waterman M, Chowers Y, Karban A, Brant SR, Silverberg MS, Gregersen PK, Katz S, Lifton RP, Zhao H, Nunez G, Pe’er I, Peter I, Cho JH. Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-kB pathway gene, HEATR3. Genes and Immunity, epublished April 25, 2013. PMCID: PMC Journal – In Process. Kenny EE, Pe’er I, Karban A, Ozelius L, Mitchell AA, Ng SM, Erazo M, Ostrer H, Abraham C, Abreu MT, Atzmon G, Barzilai N, Brant S, Burns ER, Chowers Y, Clark LN, Darvasi A, Doheny D, Duerr RH, Eliakim R, Giladi N, Gregersen PK, Hakonarson

 

H, Jones MR, McGovern DPB, Mulle J, Orr-Urtreger A, Proctor DD, Pulver A, Rotter JI, Silverberg MS, Ullman T, Warren ST, Waterman M, Zhang W, Bergman A, Mayer L, Katz S, Desnick RJ, *Cho JH, *Peter I. A Genome-Wide Scan of Ashkenazi Jewish Crohn’s Disease Suggests Novel Susceptibility Loci *shared corresponding authors. Plos Genetics 2012; 8: e1002559. PMCID:PMC3297573 6. Gathungu G, Zhang CK, Zhang W, Cho JH. A two-marker haplotype in the IRF5 gene is associated with Inflammatory Bowel Disease in a North American cohort. Genes and Immunity, 2012; 13: 351-5. (PMID: 222578939) 7. Kang J, Kugathasan S, Georges M, Zhao H, Cho JH, the NIDDK IBD Genetics Consortium. Improved risk prediction for Crohn’s disease with a multi-locus approach. Hum Mol Genet 2011; 20: 2435-42. PMCID: PMC3298027 8. Chen M, Cho J, Zhao H. Incorporating biological pathways via a Markov random field model in genome-wide association studies. Plos Genet; 2011; 7: e1001353. PMCID: PMC3072362. 9. Zenewicz L, Abraham C, Flavell RA, Cho JH. Unravelling the genetics of autoimmunity. Cell 2010; 140: 791-7. PMCID: PMC3491807 10. Ferguson JP, Cho JH, Zhao H. A new approach for the joint analysis of multiple Chip-Seq libraries with application to Histone Modification, Statistical Applications in Genetics and Molecular Biology, 2012; 11: 1544. (PMID: 22499701) 11. Abraham C and Cho JH. Mechanisms of Disease: Inflammatory Bowel Disease. New England Journal of Medicine 2009; 361: 2066-78. PMCID: PMC3491806 12. Silverberg MS*, Cho JH*, McGovern DPB, Wu J, Achkar JP, Xu W, Scott R, Barmada MM, Keli L, Daly MJ, Abrahm C, Bayless TM, Griffiths AM, Ippoliti AF, Lahaie RG, Pare P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kostner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR,   121

Taylor KD, Rioux JD, Roeder K, Duerr RH. Ulcerative colitis loci on chromosomes 1p36 and 12q15 identified by genomewide association study". *equal contributions. Nature Genetics 2009; 41: 216-20 PMCID: PMC2652837. 13. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee A, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene. Science. 2006; 314: 1461-1463 (PMID: 17068223). 14. Li J, Moran T, Swanson E, Julian C, Harris J, Bonen DK, Hedl M, Nicolae DL, Abraham C, Cho JH. Regulation of IL-8 and IL-1b expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet. 2004; 13(16):1715-1725. (PMID: 15198989) 15. *Ogura Y, *Bonen D, Inohara N, Nicolae DL, Chen F, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr R, Ackhar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH. A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease. Nature 2001;411:603 – 606 (PMID: 11385577).

BIOGRAPHICAL SKETCH NAME Clemente Litran, Jose Carlos EDUCATION/TRAINING INSTITUTION AND LOCATION Universidad de Sevilla (Spain) Japan Advanced Institute of Science and Technology (Japan) Japan Advanced Institute of Science and Technology (Japan) A. Personal Statement High-throughput sequencing technology is providing increasing amounts of data that must be turned into actionable knowledge in the clinic, the laboratory and the field. Studies of the microbiome in particular have greatly benefited from this flow of information, allowing us to understand the true extent of microbial diversity in the human body. These studies have provided us with a baseline characterization from which we can now tackle more relevant questions on the relation between disease and imbalances in the microbiome. I have a broad background in computer science and bioinformatics, with specific training and expertise in the analysis of microbiome data, as demonstrated by my collaboration in several high-profile studies characterizing the microbiome across body sites (HMP 2012a; HMP 2012b), along time (Pantoja-Feliciano, Clemente, et al., 2012), and populations (Yatsunenko et al 2012). I am one of the main developers of QIIME (Caporaso et al., Nat Methods 2010), the BIOM format (McDonald, Clemente et al., 2012) and PICRUSt (Langille et al., 2013), widely used tools for the analysis of microbial community data. In summary, I have a demonstrated record of accomplished research projects as shown by my strong 122

POSITION TITLE Assistant Professor DEGREE B.Sc.

MM/YY 09/00

FIELD OF STUDY Computer Science

M.Sc.

03/04

Bioinformatics

Ph.D.

03/07

Bioinformatics

publication record and my contributions to the development of tools and protocols for the analysis of microbiome data, which have prepared me to contribute critically to the success of this project. B. Positions and Honors Positions and Employment 2007-2010 Japan Society for the Promotion of Science postdoctoral fellow, National Institute of Genetics (Japan). 2010-2012 Research Associate, Department of Chemistry and Biochemistry. University of Colorado. 2013-present Assistant Professor, Department of Genetics and Genomic Sciences, and Department of Medicine. Mount Sinai School of Medicine. Honors 2007 Best Ph.D. thesis award. Japan Advanced Institute of Science and Technology, School of Knowledge Science. C. Selected Peer-Reviewed Publications (selected from 36 peer-reviewed publications) Most relevant to current application 1. Leopoldo N. Segal, Alexander Alekseyenko, José C. Clemente, Rohan Kulkarni, Benjamin Wu, Samuel Chung, Kenneth Berger, Roberta Goldring, William N. Rom, Constantin

Aliferis, Martin J. Blaser, Michael D. Weiden.“Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation” Microbiome 2013, 1:19. 2. Ida G Pantoja-Feliciano*, José C. Clemente*, Elizabeth K. Costello, Maria E. Perez, Martin J. Blaser, Rob Knight, Maria G. Dominguez-Bello. “Biphasic assembly of the murine intestinal microbiota during early development”. ISME 2013, doi: 10.1038/ismej.2013.15 (*equal contribution). 3. Brian D. Muegge, Justin Kuczynski, Dan Knights, José C. Clemente, Antonio Gonzalez, Luigi Fontana, Bernard Henrissat, Rob Knight, Jeffrey I. Gordon. “Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans” Science 2011, 332(6032):970974. 4. José C. Clemente, Luke K. Ursell, Laura Wegener Parfrey, Rob Knight. “The impact of the gut microbiota on human health: an integrative view”. Cell 2012, 148(6):1258–1270. 5. The Human Microbiome Project. “Structure, Function and Diversity of the Human Microbiome in an Adult Reference Population”. Nature 2012, 486(7402):207-14. 6. The Human Microbiome Project. “A framework for human microbiome research”. Nature 2012, 486(7402):215-21. 7. Tanya Yatsunenko, Federico Rey, Mark Manary, Indi Trehan, Maria Gloria Dominguez-Bello, Robert N. Baldassano, Andrey P. Anokhin, Andrew C. Heath, Barbara Warner, Jens Reeder, Justin Kuczynski, J. Gregory Caporaso, Catherine A. Lozupone, Christian Lauber, José C. Clemente, Dan Knights, Rob Knight, Jeffrey I. Gordon. “Human gut microbiome differentiation viewed across cultures, ages and families” Nature 2012, 486(7402):222-227. Additional recent publications of importance to the field (in chronological order)

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8. José C. Clemente, Jesper Jansson, Gabriel Valiente. “Accurate taxonomic assignment of short pyrosequencing reads”. In Pacific Symposium on Biocomputing (PSB) 2010, 3–9. 9. José C. Clemente, Jesper Jansson, Gabriel Valiente. “Flexible assignment of ambiguous sequencing reads” BMC Bioinformatics 2010, 12:8. 10. Robert C. Edgar, Brian J. Haas, José C. Clemente, Christopher Quince, Rob Knight. “UCHIME improves accuracy and speed of chimera detection” Bioinformatics 2011, 27(16):2194-2200 11. Antonio Gonzalez*, José C. Clemente*, Ashley Shade*, Jessica L. Metcalf, Sejin Song, Bharath Prithiviraj, Rob Knight. “Our microbial selves: what ecology can teach us. EMBO Reports 2011, 12(8):775-784. (*equal contribution) 12. Martin J. Blaser, Maria G. Dominguez-Bello, Monica Contreras, Magda Magris, Glida Hidalgo, Isidoro Estrada, Zhan Gao, José C. Clemente, Elizabeth K. Costello, Rob Knight. “Distinct cutaneous bacterial assemblages in a sampling of South American Amerindians and US residents”. ISME 2012, 7(1):85-95. 13. Frederic A. Carvalho, Omry Koren, Malin Johansson Ilke Nalbantoglu, Jesse D. Aitken, Yueju Su, William A. Walters, Antonio González Peña, José C. Clemente, Nicolas Barnich, Arlette Darfeuille-Michaud, Matam Vijay-Kumar, Rob Knight, Ruth E. Ley, and Andrew T. Gewirtz. “Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice”. Cell Host & Microbe 2012, 12(2):139152. 14. Simone S. Stahringer, José C. Clemente, Robin P. Corley, John Hewitt, Dan Knights, William A. Walters, Rob Knight and Kenneth S. Krauter. “Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood”. Genome Research 2012, 22(11):2146-2152.

15. Daniel McDonald*, José C. Clemente*, Justin Kuczynski, Jai Ram Rideout, Jesse Stombaugh, William A. Walters, Doug Wendel, Andreas Wilke, Susan Huse, Mitch Sogin, Folker Meyer, Rob Knight, and J. Gregory Caporaso. “The Biological Observation Matrix (BIOM) Format or: How I Learned To Stop Worrying and Love the Ome-ome” GigaScience 2012, 1:7. (*equal contribution) 16. Scott T. Bates, José C. Clemente, Gilberto Flores, William Anthony Walters, Laura 17. Wegener Parfrey, Rob Knight, and Noah Fierer. “Global biogeography of highly diverse protistan communities in soil”. ISME 2013 7(3):652–659. 18. Fierer N, Ladau J, Clemente JC, Leff JW, Owens SM, Pollard KS, Knight R, Gilbert JA, McCulley RL. “Reconstructing the microbial diversity and function of pre-agricultural tallgrass prairie soils in the United States” Science 2013 342(6158):621624. 19. Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL, Clemente JC, Knight R, Heath AC, Leibel RL, Rosenbaum M, Gordon JI. “The long-term stability of the human gut microbiota”. Science 2013, 341(6141):1237439. 20. Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL, Knight R, Beiko RG, Huttenhower C. “Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nature Biotechnology 2013, 31(9):814-21. 21. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI. “Gut microbiota from twins discordant for obesity modulates metabolism in mice”. Science 2013, 341(6150):1241214.

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D. Research Support Completed Research Support Japan Society for the Promotion of Science (PI: Clemente) 20082010 Kaken-hi Research Grant [ID: P08086]: “Mechanisms of evolution of metabolic pathways: characterization in green sulfur bacteria metabolism and xenobiotic degradation pathways” The goal of this project was to study mechanisms of metabolic pathway evolution utilizing two models of particular interest: green sulfur bacteria and bacterial pathways of xenobiotic degradation. This study resulted in the development of an optimized method to reconstruct ancestral states, which allowed us to work with larger datasets at a fraction of the computational cost. National Institute of Genetics (Japan) (PI: Clemente) 20112012 Collaborative Research Grant [ID: B10-2011]: “The Rice Microbiome Project” The goal of this project was to characterize the evolution of bacterial communities in bulk soil and rhizhosphere of four different rice cultivars, from seedling to harvest. We are currently characterizing how the changes observed in the microbiome of these rice varieties are related to developmental stage, nutrient conditions, and pH. University of Colorado (PI: R. Knight) 2011-2013 Janus supercomputer allocation grant [ID: UCB00000015]: “QIIME parameter sweep” The objective of this study was to determine the effect that different parameters in the QIIME pipeline have when analyzing microbiome data. In particular, we measured how diversity estimates, taxonomic assignment, and predictive accuracy are affected by the particular choice of parameter values in QIIME.

 

BIOGRAPHICAL SKETCH NAME Colombel, Jean Frederic EDUCATION/TRAINING INSTITUTION AND LOCATION Universite of Lille 2, France Universite of Lille 2, France

A. Personal Statement Over the past 20 years I have set up in Lille (France) together with my colleagues a successful comprehensive research and health care network fully dedicated to Inflammatory Bowel Diseases (Crohn’s disease [CD] and ulcerative colitis [UC]). Our research centre was composed of 3 complementary groups: (1) a medical and surgical department which has performed many multicentre studies at the national (GETAID group) and international level; (2) an epidemiological group based upon the IBD North-Western Registry (EPIMAD); (3) a physiopathological group devoted to the study of immunological mechanisms and the development of new therapeutic targets in regulation of digestive inflammation. Thanks to the development of multiple local, national and international collaborations we have been able to make some important contributions to the pathophysiology of IBD. The most remarkable are the initiation in 1994 of collection and sampling of IBD families that eventually led to the identification of NOD2 as a susceptibility gene for CD, the development in the 90’s of the ASCA test (antiS. cerevisiae (mannan) antibodies) which is still the most sensitive and specific serologic marker for CD and elucidation of the potential role of Candida albicans in CD and the identification of a new pathovar of Escherichia coli (AIEC for 125

POSITION TITLE Associate Professor DEGREE M.D. Research Habilitation

YEAR(s) 1984 1990

FIELD OF STUDY Hepatogastroenterology Hepatogastroenterology Mucosal Immunology

adhesive invasive E.coli) associated with ileal CD. At the national level, I have been one of the leaders of the GETAID group, initiating and participating to many clinical trials that have helped to improve therapeutic strategies in IBD especially regarding the use of immunomodulators and biologics. Apart from international recognition, one of the biggest achievement of the GETAID has been the emergence of a new generation of young and bright European gastroenterologists with an interest in IBD. At the international level I have been involved as participant or primary investigator in most recent therapeutic trials with biologics. The main concretisation of this work has been the publication as primary author or co-author of more than 500 peer-reviewed papers and 30 chapters of books most of them in the domain of IBD. I have been invited to give talks in many countries either during IBD meetings or national and international meetings including UEGW and DDW. I have been and am still in the editorial board of several gastroenterology journals including Clinical Gastroenterology and Hepatology, Nature reviews in Gastroenterology and Hepatology, Inflammatory Bowel Disease and Journal of Crohn’s and Colitis. I have been associate editor of Gut from 2005 to 2009 and I am currently associate editor of Alimentary Pharmacology and Therapeutics being in charge of

IBD papers. This leadership in IBD has been recognized by my friends and colleagues who elected me as the president of ECCO (2008-2010) and chair of the International Organisation of Inflammatory Bowel Disease (IOIBD) (2010-current). I have been appointed at the director of the Helmsley IBD centre at Mount Sinai on January 1, 2013. B. Positions and Honors 1991-2011 Professor of Hepatogastroenterology, CHRU Lille, France 6/2002-12/2002 Visiting Professor at Mayo Clinic, Rochester, USA 2005- 2012 Head Epidemiologic Registry of IBD for Northern France (EPIMAD) (INSERM, IVS) 2009 Recipient of the United European Gastroenterology Federation Research Prize for 2009 2010-2012 President Groupe d’Etudes Therapeutiques des Maladies Inflammatoires Digestives (GETAID) 2010-2012 President European Crohn’s Colitis Organization (ECCO) 2010-ongoing Chair International Organization of Inflammatory Bowel disease 1.2011-1.2012 Visiting professor, Mount Sinai School of Medicine, New York 2012 Head, Department of Hepatogastroenterology, CHU Lille, France. 2013 – present Director Helmsley Inflammatory Bowel Disease Centre, Department of Gastroenterology, Icahn School of Medicine at Mount Sinai C. Selected Peer-reviewed Publications 1. Peyrin-Biroulet L, Desreumaux P, Sandborn WJ, Colombel JF. Crohn's disease: beyond antagonists of tumour necrosis factor. Lancet. 2008;372:67-81. PMID: 1860361 2. Colombel JF, Watson AJ, Neurath MF. The 10 remaining  

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mysteries of inflammatory bowel disease. Gut. 2008 ; 57:429-33. PMID: 18079284 Vernier-Massouille G, Balde M, Salleron J, Turck D, Dupas JL, Mouterde O, Merle V, Salomez JL, Branche J, Marti R, Lerebours E, Cortot A, Gower-Rousseau C, Colombel JF. Natural History of Pediatric Crohn's Disease: A PopulationBased Cohort Study. Gastroenterology 2008;135:1106-13. PMID: 18692056 Colombel JF, Schwartz DA, Sandborn WJ, Kamm MA, D'Haens G, Rutgeerts P, Enns R, Panaccione R, Schreiber S, Li J, Kent JD, Lomax KG, Pollack PF. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut 2009;58:940-8. PMCID: PMC2689393 Sandborn WJ, Rutgeerts P, Feagan BG, Reinisch W, Olson A, Johanns J, Lu J, Horgan K, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 2009;137:1250-60. PMID: 15996014 Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383-95. PMID: 20393175 Chassaing B, Rolhion N, de Vallee A, Salim SY, Prorok-Hamon M, Neut C, Campbell BJ, Soderholm JD, Hugot JP, Colombel JF, Darfeuille-Michaud A. Crohn disease--associated adherent-invasive E. coli bacteria target mouse and human Peyer's patches via long polar fimbriae. J Clin Invest 2011;121:966-75. PMCID: PMC3049390 Colombel JF, Rutgeerts P, Reinisch W, Esser D, Wang Y, Lang Y, Marano CW, Strauss R, Oddens BJ, Feagan BG, Hanauer SB,

 

Lichtenstein GR, Present D, Sands BE, Sandborn WJ. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011;141:1194-201. PMID: 21723220 9. Louis E, Mary JY, Vernier-Massouille G, Grimaud JC, Bouhnik Y, Laharie D, Dupas JL, Pillant H, Picon L, Veyrac M, Flamant M, Savoye G, Jian R, Devos M, Porcher R, Paintaud G, Piver E, Colombel JF*, Lemann M*. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012;142:63-70. PMID:2154593 10. Laharie D, Bourreille A, Branche J, Allez M, Bouhnik Y, Filippi J, Zerbib F, Savoye G, Nachury M, Moreau J, Delchier JC, Cosnes J, Ricart E, Dewit O, Lopez-Sanroman A, Dupas JL, Carbonnel F, Bommelaer G, Coffin B, Roblin X, Van Assche G, Esteve M, Färkkilä M, Gisbert JP, Marteau P, Nahon S, de Vos M, Franchimont D, Mary JY, Colombel JF*, Lémann M*. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 2012;380:1909-15. PMID: 215603316 11. Sandborn WJ, Colombel JF, Sands BE, Rutgeerts P, Targan SR, Panaccione R, Bressler B, Geboes K, Schreiber S, Aranda R, Gujrathi S, Luo A, Peng Y, Salter-Cid L, Hanauer SB. Abatacept for Crohn's Disease and Ulcerative Colitis. Gastroenterology 2012; 143:62-69. PMID: 22504093 12. Desreumaux P, Foussat A, Allez M, Beaugerie L, Hebuterne X, Bouhnik Y, Nachury M, Brun V, Bastian H, Belmonte N, Ticchioni M, Duchange A, Morel-Mandrino P, Neveu V, Clerget-Chossat N, Forte M, Colombel JF. Safety and Efficacy of Antigen-Specific Regulatory T-Cell Therapy for Patients with Refractory Crohn's Disease. Gastroenterology

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2012;143:1207-17. PMID: 22885333 13. Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, Rousseaux C, Dubuquoy C, Decourcelle C, Saudemont A, Tachon M, Béclin E, Odou MF, Neut C, Colombel JF, Desreumaux P. Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn's disease. Gut. 2012;61:7885. PMCID: PMC3230831 14. Hébuterne X, Lémann M, Bouhnik Y, Dewit O, Dupas JL, Mross M, D'Haens G, Mitchev K, Ernault E, Vermeire S, BrixiBenmansour H, Moreels TG, Mary JY, Marteau P, Colombel JF. Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol. Gut 2013;62:201-8. PMCID: PMC3551215 15. Charpentier C, Salleron J, Savoye G, Fumery M, Merle V, Laberenne JE, Vasseur F, Dupas JL, Cortot A, Dauchet L, Peyrin-Biroulet L, Lerebours E, Colombel JF, GowerRousseau C . Natural history of elderly-onset inflammatory bowel disease: A population-based cohort study. Gut 2013; in press. * : equal contribution

 

BIOGRAPHICAL SKETCH NAME Cortes, Patricia EDUCATION/TRAINING INSTITUTION AND LOCATION Universidad Austral, Chile Universidad Austral, Chile UMDNJ-Robert Wood Johnson Medical School, NJ A. Personal Statement My laboratory investigates the mechanism and regulation of V(D)J recombination and DNA repair. Our group was the first to demonstrate that RAG2 C-terminus bridges the RAG recombinase with chromatin through histone interaction. In a more recent study, we showed that mutations in the PHD domain of RAG2, identified in patients with SCID and Omenn Syndrome, affected its stability, cellular localization and histone interaction. My group has also characterized the nuclease activity of the RAG recombinase and contributed to the limited number of publications describing the biochemical properties of full-length RAGs. In the past few years we expanded our studies to investigate the mechanistic and regulatory roles of Artemis and Ligase IV on V(D)J recombination and DNA repair, two processes that are linked by the generation of double strand breaks and the participation of non-homologous end joining proteins in repairing the DNA breaks. Our most recent work demonstrated a key role for Artemis in facilitating efficient V(D)J recombination; a function that is mediated by the interaction of the Artemis C-terminal with DNA ligase IV and DNA-PKcs. An important link between the processing and repair factors of V(D)J recombination and DNA repair was demonstrated by our findings. The Artemis-

POSITION TITLE Associate Professor DEGREE B.S.

YEAR(s) 1981-1984

FIELD OF STUDY Biochemistry

M.S. Ph.D.

1984-1985 1987-1991

Biochemistry Biochemistry and Molecular Biology

DNA Ligase IV interaction was mapped to an 11 aa peptide on Artemis and to the DNA binding domain of DNA Ligase IV. In collaboration with the laboratory of Dr. Aneel Aggarwal, we solved the structure of this complex. In summary, my group has contributed to understanding the mechanism and regulation of V(D)J recombination as well as DNA repair. In addition, we have provided training and career development for numerous postdocs, Ph.D. students, college and high school students. Among a total of 29 trainees (four of which were high school students), 15 were women and 11 were underrepresented minorities. My group has and will continue to educate future generation of scientists while maintaining a strong commitment to research. B. Positions and Honors Positions and Employment 1991-1995 Postdoctoral Fellow, Rockefeller University New York, New York (Dr. David Baltimore) 1995-1996 Postdoctoral Fellow, Rockefeller University

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New York, New York (Dr. Michel Nussenzweig) Research Associate, Rockefeller University New York, New York (Dr. Michel Nussenzweig) Assistant Professor (non-tenure track), Rockefeller University New York, New York (Dr. Michel Nussenzweig’s laboratory) 1999-2010 Assistant Professor, Mount Sinai School of Medicine New York, New York 2010-Present Associate Professor, Icahn School of Medicine at Mount Sinai New York, New York 1982, 1983 and 1984 Undergraduate Scholarship. Award to the Honors and Awards best student of the Science School. Universidad Austral de Chile. 1988 Graduate Fellowship from Hoechst Celanese Corporation. 1989 Graduate Fellowship from the Kirin Brewery Corporation. Postdoctoral Fellowship from the Irvington Institute. 1995-1996 Postdoctoral Fellowship from the Lymphoma Research Foundation of America. 1998-1999 Arthritis Investigator Award from the Arthritis Foundation. 1999-2003 Cancer Research Institute Investigator Award. 2001-2006 The Leukemia and Lymphoma Society Scholar Award. 2004-2008 American Cancer Society Research Scholar Award. 2006-2011 The Irma T. Hirschl/Monique Weill-Caullier Research Award. 1995

 

2009 Best mentor award. Mount Sinai School of Medicine. Nominated by the students. 2012 Outstanding Teaching Award, MSSM. Given by the Student Council. Service 2000-2003 Co-Director of the Molecular, Cellular, Biochemical and Developmental Sciences Training Area. Mount Sinai School of Medicine. 2000-2003 Course Director for Advanced Topics in Molecular, Cellular, Biochemical and Developmental Sciences. 2007-2012 Founding Co-Director of the Immunology Training Area. Mount Sinai School of Medicine. 2007-2012 Course Co-Director for Journal Club in Immunology 2011-2013 Associate Director and member of the steering committee and admissions committee for the PREP (Postbaccalaureate education program) program. 2012-Present Course Director for Advanced Topics in Immunology 2011-2012 Co-Guest Editor for volume 54 of Immunologic Research featuring the immunology program at Mount Sinai. Ad-hoc reviewer for scientific projects: NIH, Allergy and Immunology study section; NIH, National Cancer Institute; NIH, Board of Scientific Counselors for National Institute of Arthritis and Musculoskeletal and Skin Diseases, Intramural Program; The Wellcome Trust, UK; Fondo Nacional de desarrollo Cientifico y Tecnologico, Chile; Center for Disease Prevention and Control. Investigation on Primary Immunodeficiency, ZRG1 IMM-N(52)R, 5/2012 and 9/2013. Cellular and Molecular Immunology (CMIB), 2/2013. 8

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Ad-hoc reviewer for scientific Journals: Genes and Development, Journal of Biological Chemistry, Journal of Experimental Medicine, Journal of Clinical Investigation, Journal of Immunology, Molecular and Cell Biology, Molecular Cell, Nature Structural Biology, Nature Communications, Journal of Allergy and Clinical Immunology, Nucleic Acid Research, PNAS, Gene and Gastroenterology. Member of the American Association of Immunology Committee on the Status of Women (2009-2012) C. Publications (15 out of 27 publications are presented) 1. Sawchuk, D., Weis-Garcia, F., Malik, S., Besmer, E., Bustin, M., Nussenzweig, M., and Cortes, P. (1997). V(D)J recombination: Modulation of RAG1 and RAG2 cleavage activity on 12/23 substrates by whole cell extract and DNAbinding proteins. J. Exp. Med. 185, 2025-2032. 2. Weis-Garcia, F., Besmer, E., Yu, W., Sawchuk, D., Hu, Y., Nussenzweig, M., and Cortes, P. (1997). V(D)J recombination: in vitro coding joint formation. Mol. Cel. Biol. 17, 6379-6385. 3. Besmer, E., Mansilla-Soto, J., Cassard, S., Sawchuk, D., Brown, g., Sadofsky, M., Lewis, S., Nussenzweig, M., and Cortes, P. (1998). Hairpin coding end opening is mediated by RAG1 and RAG2 proteins. Molecular Cell. 2, 817-828. 4. Santagata, S., Besmer, E., Villa, A., Bozzi, F., Allingham, J., Sobacchi, C., Haniford, D., Vezzoni, P., Nussenzweig, M., Pan, Z-Q., and Cortes, P. (1999). The RAG1/RAG2 complex constitues a 3’ flap endonuclease: implications for junctional diversity in V(D)J and transpositional recombination. Molecular Cell 4, 935-947. 5. Santagata, S., Gomez, C. A., Sobacchi, C., Bozzi, F., Abinum, M., Pasic, S., Cortes, P., Vezzoni, P., and Villa, A. (2000). Nterminal RAG1 frameshift mutations in Omenn’s syndrome:

6. 7.

8.

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10.

11.

internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Proc. Natl. Acad. Sci. USA 19, 14572-14577. Mansilla-Soto, J., and Cortes, P. (2003). Commentary. VDJ Recombination: Artemis and Its In Vivo Role in Hairpin Opening. J. Exp. Med. 197, 543-547. Sawchuk, D. J., Mansilla-Soto, J., Alarcon, C., Singha, N. C., Langen, H., Bianchi, M.E., Lees-Miller, S. P., Nussenzweigh, M. C., and Cortes, P. (2004). Ku70/80 and DNA-PKcs modulate RAG-mediated cleavage. Implications for the enforcement of the 12/23 rule. JBC, 279; 29821-29831. West, K.L., Singha, N.C., De Ioannes, P., Lacomis, L., Erdjument-Bromage, H. Tempst, P., and Cortes, P. (2005). A direct interaction between RAG2 C-terminus and the core histones is required for VH to DJH recombination. Immunity. 23; 203-212. Matangkasombut, P., Pichavant, M., Saez, D.E., Giliani, S., Mazzolari, E., Finocchi, A., Villa, A., Cortes, P., Umetsu, D.T., and Notarangelo, L. (2008). Lack of iNKT cells in patients with combined immune deficiency due to hypomorphic RAG mutations. Blood 111, 271-274. Couedel, C., Roman, C., Jones, A., Vezzoni, P., Villa, A., and Cortes, P. (2010). Analysis of mutations from SCID and Omenn syndrome patients reveal the central role of the Rag2 PHD domain in regulating V(D)J recombination. Journal of Clinical Investigation. 120; 1337-1344. Artemis C-terminal region facilitates V(D)J recombination through its interactions with DNA Ligase IV and DNA-PKcs. Malu, S., De Ioannes, P., Kozlov, M., Greene, M., Francis, D., Hanna, M., Pena, J., Escalante, C., Kurosawa, A., ErdjumentBromage, H., Tempst, p., Adachi, N., Vezzoni, P., Villa, A.,

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12. 13. 14.

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Aggarwal, A. K., Cortes, P. (2012). J. Exp. Med. 209 (5), 955963. Malu, S., Malshetty, V., Francis, D., and Cortes, P. (2012). Role of non-homologous end joining in V(D)J recombination. Immunol Res. 54, 233-246. Mayer, L.*, Lira, S., Ting, A., and Cortes, P. (2012). Introduction to the special issue on Immunology at Mount Sinai. *corresponding author. Immunol Res. 54, 1-3. De Ioannes, P., Malu, S., Cortes, P.*, and Aggarwal, AK.* (2012). Structural Basis of DNA Ligase IV-Artemis Interaction in Nonhomologous End-Joining. Cell Reports 2, 1505-15012. PMID 23219551. *corresponding authors. Recombination-activating gene1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. (2013) van Til NP., Sarwari, R., Visser, T. P., Hauer, J., Lagresle-Peyrou, C., van der Velden, G., Malshetty, V., Cortes, P., Jollet, A., Danos, O., Cassani, B., Zhang, F., Thrasher, A. J., Fontana, E., Poliani, P. L., Cavazzana, M., Verstegen, M. M., Villa, A., and Wagemaker, G. J Allergy Clin Immunol. In press; published online December 2013. PMID: 24332219.

 

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BIOGRAPHICAL SKETCH NAME Cunningham-Rundles, Charlotte

EDUCATION/TRAINING INSTITUTION AND LOCATION Duke University, North Carolina Columbia University New York University A. Personal Statement: My career has been based on work on the pathogenesis, characterization and treatment of human immune deficiency diseases. I am a Professor of Medicine, Pediatrics and Immunology at Mount Sinai Medical Center, and Program Director for Allergy Immunology Fellowship Training. I obtained my PhD in immunology, and from this beginning, fortunately found myself in the world of Primary Immune Deficiency, leading to both basic research and clinical care. I am the Principle Investigatory of the USIDNET, an NIH supported research Consortium of the Immune Deficiency Foundation. I am an internist by training but have held a pediatric appointment for many years. I established the Primary Immune Deficiency Clinic at Mount Sinai, a referral service for infants, children and adults with known or suspected primary immune deficiency diseases for the Northeast; however patients come from all over the United States and other countries. We have a long standing laboratory investigation on the defects of human immune cells, based on the genetic defects that occur in these subjects. These studies have proved of great value in  

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POSITION TITLE Professor of Medicine/Pediatrics/Immunology David S Gottesman Professor of Immunology Acting Chief, Clinical Immunology DEGREE B.S. M.D. Ph.D.

MM/YY 1965 1969 1974

FIELD OF STUDY Zoology-Chemistry Medicine Immunology

determining how normal immunity is organized and ultimately controlled. B. Positions and Honors: Professor of Medicine, Pediatrics and Immunology at Mount Sinai Medical Center 1994Program Director for Allergy Immunology Fellowship Training. 1992Fellow, American Academy Asthma Allergy Immunology Clinical Immunology Society (Secretary Treasurer 1994-1999, Elected Councilor 1999) Best Doctors in America 2000America's Top Doctors 2000- Winner of Patients' Choice Award2002 Clinical Immunology Society President 2003-2004 Founding Member USIDNet Consortium for Research 2003 Principle Investigator 2010 Chair NIH Allergy Immunology Transplantation Grant Review Chair Immunology NAR Review Committee National Aeronautics and Space Administration 2004-2006 Board of Trustees, American Academy Asthma Immunology, 2006- 2011

Clinical Immunology Society President’s Award, 2007 Boyle Award, Immune Deficiency Foundation, 2007. IUIS Expert Committee on Primary Immune Deficiency 2007Treasurer, 2011David S Gottesman Professor of Immunology 2008Jacobi Medallion, 2010; Dr Jeffrey Greene Visiting Professor Children’s Hospital of Philadelphia 2010 Robert Ellis Lecturer AAAAI 2011 American Society for Microbiology: Abbott Award in Clinical and Diagnostic Immunology, 2011. American Assoication Asthma Allergy and Immunology (AAAAI) Distinguished Clinician Award 2014 C. Selected Peer-reviewed Publications (of 215) 1. HERVÉ M, ISNARDI I, NG YS, BUSSEL JB, OCHS HD, CUNNINGHAM-RUNDLES C, MEFFRE E. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med. 2007 9;204(7):1583-93. PMC2118633 2. ZHANG L, RADIGAN L, SALZER U, BEHRENS TW, GRIMBACHER B, DIAZ G, BUSSEL J, CUNNINGHAMRUNDLES C. Transmembrane activator and calciummodulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol. 2007 Nov;120(5):1178-85. PMID: 17983875; NIHMSID # 213672; PMC2908504. 3. KNIGHT AK, RADIGAN L, MARRON T, LANGS A, ZHANG L, CUNNINGHAM-RUNDLES C. High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency. Clin Immunol. 2007;124(2):182-9. 2007. PMCID: PMC2491330 4. SÁNCHEZ-RAMÓN S, RADIGAN L, YU JE, BARD S, CUNNINGHAM-RUNDLES C. Memory B cells in common

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variable immunodeficiency: Clinical associations and sex differences. Clin Immunol. 2008 10. PMC 2692232 5. YU JE, KNIGHT AK, RADIGAN L, MARRON TU, ZHANG L, SANCHEZ-RAMOS S, CUNNINGHAM-RUNDLES C. Toll-like receptor 7 and 9 defects in common variable immunodeficiency. J Allergy Clin Immunol. 2009 Aug;124(2):349-56, 356. NIHMSID # 213680; PMC2908501. 6. CHEN K, XU W, WILSON M, HE B, MILLER NW, BENGTON E, EDHOLM ES, SANTINI PA,RATH P, CHIU A, CATTALINI M, LITZMAN J, B BUSSEL J, HUANG B, MEINI A, RIESBECK K, CUNNINGHAM-RUNDLES C, PLEBANI A, CERUTTI A. Immunoglobulin D enhances immune surveillance by activating antimicrobial, pro inflammatory and B cellstimulating programs in basophils. Nat Immunol. 2009 Aug;10(8):889-98. PMCID: PMC2785232 7. CHAPEL H, CUNNINGHAM-RUNDLES C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009 Jun;145(6):709-27. PMCID: PMC2718064 8. ISNARDI I, NG YS, MENARD L, MEYERS G, SAADOUN D, SRDANOVIC I, SAMUELS J, BERMAN J, BUCKNER JH, CUNNINGHAM-RUNDLES C, MEFFRE E. Complement receptor2/CD21-negative human naive B cells mostly contain autoreactive unresponsive clones. Blood. 2010 Mar 15. PMID: 20231422. 9. CUNNINGHAM-RUNDLES C. How I treat common variable immune deficiency. Blood. 2010 Mar 23. PubMed PMID: 20332369; PMCID: PMC2904582 10. HE B, SANTAMARIA R, XU W, COLS M, CHEN K, PUGA I, SHAN M, XIONG H, BUSSEL JB, CHIU A, PUEL A, REICHENBACH J, MARODI L, DOFFINGER R, VASCONCELOS J, ISSEKUTZ A, KRAUSE J, DAVIES G, LI X, GRIMBACHER B,

 

PLEBANI A, MEFFRE E, PICARD C, CUNNINGHAM-RUNDLES C, CASANOVA JL, CERUTTI A. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat Immunol. 2010 Sep;11(9):836-45. Epub 2010 Aug 1. PubMed PMID: 20676093. PMCID: PMC3047500 11. PARK JH, RESNICK ES, CUNNINGHAM-RUNDLES C. Perspectives on common variable immune deficiency. Ann N Y Acad Sci. 2011 1246(1):41-9..1749-6632.2011.06338. PubMed PMID: 22236429. PMC3428018 12. MARRON TU, YU JE, CUNNINGHAM-RUNDLES C. Toll-like receptor function in primary B cell defects. Front Biosci (Elite Ed). 2012 Jan 1;4:1853-63. PubMed PMID: 22202002; PMC2941555. 13. RESNICK ES, MOSHIER EL, GODBOLD JH, CUNNINGHAMRUNDLES C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2011 Dec 16. PubMed PMID: 22180439. 14. CHINEN J, MARTINEZ-GALLO M, GU W, COLS M, CERUTTI A, RADIGAN L, ZHANG L, POTOCKI L, WITHERS M, LUPSKI JR, CUNNINGHAM-RUNDLES C. Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B-cell dysfunction in patients with Smith-Magenis syndrome. J Allergy Clin Immunol. 2011 Jun;127(6):1579-86. PMID: 21514638. PMC3428026 15. ORANGE JS, GLESSNER JT, RESNICK E, SULLIVAN KE, LUCAS M, FERRY B, KIM CE, HOU C, WANG F, CHIAVACCI R, KUGATHASAN S, SLEASMAN JW, BALDASSANO R, PEREZ EE, CHAPEL H, CUNNINGHAM-RUNDLES C, HAKONARSON H. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol. 2011;127(6):1360-7. PubMed PMID: 21497890. NIHMS281974

 

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16. MARRON TU, MARTINEZ-GALLO M, YU JE, CUNNINGHAMRUNDLES C. Toll-like receptor4-, 7-, and 8-activated myeloid cells from patients with X-linked agammaglobulinemia produce enhanced inflammatory cytokines. J Allergy Clin Immunol. 2012 Jan;129(1):184-190. PubMed PMID: 22088613. PMC3428022 17. YU JE, ZHANG L, RADIGAN L, SANCHEZ-RAMON S, CUNNINGHAM-RUNDLES C. TLR-mediated B cell defects and IFN-alpha in common variable immunodeficiency. J Clin Immunol. 2012 Feb;32(1):50-60. PubMed PMID: 22048980. 18. GOBERT D, BUSSEL JB, CUNNINGHAM-RUNDLES C, GALICIER L, DECHARTRES A, BEREZNE A, BONNOTTE B, DEREVEL T, AUZARY C, JAUSSAUD R, LARROCHE C, LEQUELLEC A, RUIVARD M, SEVE P, SMAIL A, VIALLARD JF, GODEAU B, HERMINE O, MICHEL M. Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients. Br J Haematol. 2011 155(4):498-508. PMID: 21981575. 19. MEYERS G, NG YS, BANNOCK JM, LAVOIE A, WALTER JE, NOTARANGELO LD, KILIC SS, AKSU G, DEBRE M, RIEUXLAUCAT F, CONLEY ME, CUNNINGHAM-RUNDLES C, DURANDY A, MEFFRE E. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc Natl Acad Sci U S A. 2011 108(28):11554-9. Jun 23. PubMed PMID: 21700883; PMCID: PMC3136251. 20. CUNNINGHAM-RUNDLES C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012; 2012:301-5. asheducation-2012.1.301. PubMed PMID: 23233596. 21. RESNICK ES, MOSHIER EL, GODBOLD JH, CUNNINGHAMRUNDLES C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012 Feb

16;119(7):1650-7. doi: 10.1182/blood-2011-09-377945. Epub 2011 Dec 16. PubMed PMID: 22180439; PMCID: PMC3286343 22. MARTINEZ-GALLO M, RADIGAN L, ALMEJIN MB, MARTINEZPOMAR N, MATAMOROS N, CUNNINGHAM-RUNDLES C. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013 131(2):468-76. doi:10.1016/j.jaci.2012.10.029.Epub 2012 Dec 11.PubMedPMID: 23237420. 23. WALEED AL-HERZ AB, JEAN-LAURENT CASANOVA, HELEN CHAPEL, MARY ELLEN CONLEY, CHARLOTTE CUNNINGHAM-RUNDLES, AMOS ETZIONI, ALAIN FISCHER, JOSE LUIS FRANCO, RAIF S. GEHA, LENNART HAMMARSTRÖM, SHIGEAKI NONOYAMA, LUIGI DANIELE NOTARANGELO, HANS DIETER OCHS, JENNIFER M. PUCK, CHAIM M. ROIFMAN , REINHARD SEGER AND MIMI L. K. TANG. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol. 2011; Nov 8. 2011; PMCID: PMC3342372

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BIOGRAPHICAL SKETCH NAME Stephanie Dahan EDUCATION/TRAINING INSTITUTION AND LOCATION University of Sciences, Nice-France

DEGREE M.Sc.

YEAR(s) 1997

University of Sciences, Marseille-France

Ph.D.

2002

Mount Sinai School of Medicine

Post-doc

2008

A. Personal Statement: I have focused my research on the description of the central role of epithelial cells in homeostasis and disease states. I have extensive expertise in manipulating intestinal epithelial cells and lamina propria lymphocytes isolated from human intestinal resection and studying their molecular crosstalk. In addition, I developed murine models of colitis where permeability and tight junctions played a major role. Thus, I have the required experience to oversee the proposed project. B. Positions and Honors: Research Experience: 1998-2002 Graduate Student, Laboratoire de Gastroentérologie et Nutrition, Nice, France 2004-2008 Postdoctoral fellow, Immunobiology Center, Mount Sinai School of Medicine, New York, USA 2008-2011 Instructor, Immunology Institute, Mount Sinai School of Medicine, New York, USA 2011-current Assistant Professor of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA Honors:   136

POSITION TITLE Assistant Professor FIELD OF STUDY Biochemistry Life Sciences, Cellular and Molecular Nutrition Immunology

1999-2002 Fellowship provided by the Laboratoires Biocodex and the Région Provence-Alpes Côte d’Azur 2002 Travel Award for the Journées Francophones de Pathologies Digestives 2009-2012 Career Development Award granted by the Crohn’s and Colitis Foundation of America (CCFA) 2010 Young Investigator’s Award granted by the Crohn’s and Colitis Foundation of America (CCFA) 2012, 2013 Poster of Distinction awarded by the American Gastroenterology Association (AGA) Institute Other Experience 2006- Reviewer for Gastroenterology 2011- Reviewer for Journal of Digestive Diseases 2011- Reviewer for Mucosal Immunology 2012- Reviewer for Plos One 2012- Reviewer for the Israel Science Foundation 2012- Reviewer for the Netherlands Organization for Scientific Research 2013- Reviewer for Inflammatory Bowel Diseases 2014- Reviewer for PeerJ Memberships 2005- Society for Mucosal Immunology

2006- American Gastroenterological Association 2008- New York Academy of Science Publications: 1. Czerucka D., Dahan S., Mograbi B., Rossi B. and Rampal P. Saccharomyces boulardii preserves barrier function and modulates the signal transduction pathway induced in EPEC-infected T84 cells. Infect. Immun. 2000. 68: 59986004. PMID: 10992512 2. Czerucka D., Dahan S., Mograbi B., Rossi B. and Rampal P. Implication of MAPK in T84 cell responses to EPEC infection. Infect. Immun. 2001. 69: 1298-1305. PMID: 11179291 3. Dahan S., Busuttil V., Imbert V., Peyron JF, Rampal P., and Czerucka D. EHEC induce IL-8 production via activation of MAPK and the transcription factors NK-κB and AP-1 in T84 cells. Infect. Immun. 2002. 70: 2304-2310. PMID: 11953364 4. Dahan S., Dalmasso G., Imbert V., Peyron JF, Rampal P., and Czerucka D. Saccharomyces boulardii interferes with EHECinduced signaling pathways in T84 cells. Infect. Immun. 2003. 71: 766-773. PMID: 12540556 5. Dalmasso G., Loubat A., Dahan S., Calle G., Rampal P., and Czerucka D. Saccharomyces boulardii prevents TNFα induced apoptosis in EHEC-infected human colonic cell line T84. Res. Microbiol. 2006. 157: 456-465. PMID: 16487684 6. Li H., Nowak-Wegrzyn A., Charlop-Powers Z., Shreffler W., Chehade M., Thomas S., Roda G., Dahan S., Sperber K. and Berin M.C. Transcytosis of IgE-mediated complexes by CD23a in human intestinal epithelial cells and its role in food allergy. Gastroenterol. 2006. 131: 47-58. PMID: 16831589 7. Dahan S., Roth-Walter F, Arnaboldi, P., Agarwal, S., and Mayer L. Epithelial: lymphocytes interactions in the gut. Immunol. Rev. 2007. 215: 243-253. PMID: 17291293

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8. Dahan S., Roda G., Pinn D., Roth-Walter F., Kamalu O., Martin A.P., and Mayer L. Epithelial:lamina propria lymphocyte interactions promote epithelial cell differentiation. Gastroenterol. 2008. 134: 192-203. PMID: 18045591 9. Roth-Walter F., Berin M.C., Arnaboldi P., Escalante C.R., Dahan S., Jensen-Joralim E., and Mayer L. Pasteurization of β-lactoglobulin promotes allergic sensitization in mice by enhancing uptake through Peyer’s patches. Allergy. 2008. 63(7): 882-90. PMID: 18588554 10. Dahan S., Roth-Walter F., Martin AP., Arnaboldi P., Mayer L. Lymphoepithelial interactions: a new paradigm. Ann N Y Acad Sci. 2009. 1165: 323-6. PMID: 19538323 11. Roda G.*,Dahan S.*, Mezzanotte L., Caponi A., Roth-Walter F., Pinn D., and Mayer L. The defect in CEACAM family member expression in Crohn’s disease IECs is regulated by the transcription factor SOX9. Inflamm. Bow. Dis. 2009. 15(12): 1775-1783. PMID: 19637360 (*Authors equally contributed) 12. Nguyen HT., Dalmasso G., Yan Y., Laroui H., Dahan S., Mayer L., Sitaraman SV., Merlin D. MicroRNA-7 modulates CD98 expression during intestinal epithelial cell differentiation. J. Biol. Chem. 2010. 285(2): 1479-89. PMID: 19892711 13. Dahan S., Rabinowitz KM., Martin AP., Berin MC., Unkeless JC, Mayer L. The Notch-1 signaling pathway regulates intestinal epithelial barrier function in mice and humans through interaction with CD4+ T cells. Gastroenterol. 2011.140: 550-559. PMID: 21056041 14. Laitman LE. and Dahan, S. Taking inflammatory bowel disease up a Notch. Immunologic Research. 2012 Dec;54(13):69-74. PMID: 22427015 15. Rabinowitz KM., Wang Y., Chen E., Hovhannisyan Z., Chiang D., Berin MC., Dahan S., Chaussabel D., Ma’ayan A. and

Mayer L. TGFβ signaling controls the activity of human intestinal CD8+ T suppressor cells. Gastroenterol 2013 Mar;144(3):601-612. PMID: 23232296 16. Song Y.*, Dunkin DS.*, Dahan S., Iuga A., Ceballos C., Yang N., Benkov K., Mayer L., Li XM. Anti-inflammatory Effects of the Chinese Herbal Formula FAHF-2 in Experimental and

  138

Human IBD. Inflamm. Bow. Dis. 2013. Nov 18. PMID: 24252977 (*Authors equally contributed) 17. Mathern DR.*, Laitman LE.*, Hovhannisyan Z., Dunkin D., Farsio S., Malik TJ., Roda G., Chitre A., Iuga AC., Yeretssian G., Berin MC., Dahan S. Mouse and human Notch-1 regulate mucosal immune responses. Mucosal Immunology. 2014 Jan 15. PMID: 24424521 (*Authors equally contributed)

 

BIOGRAPHICAL SKETCH NAME Davies, Terry Francis

EDUCATION/TRAINING INSTITUTION AND LOCATION University of Newcastle-upon-Tyne, UK Royal College of Physicians, London, UK University of Newcastle-upon-Tyne, UK Royal College of Physicians, London, UK A. Personal Statement I am the Florence and Theodore Baumritter Professor of Medicine and currently the Director of the Division of Endocinology and Metabolism at the James J Peters VA Medical Center. I have been funded continuously by NIH-NIDDK since 1980 and I have published over 450 papers, chapters and books in the area of endocrine cell biology with an emphasis on the thyroid cell and thyroid autoimmunity. I am a member of the American Association of Physicians and recipient of the John B Stanbury Gold Medal of the American Thyroid Association for our work on thyroid physiology and pathophysiology. I am a Past President of the American Thyroid Association. I currently devote my time to research, clinical practice and teaching. We have a long-standing interest in developing an ES cell-based model for studying thyroid development and are in an excellent position to pursue the objectives outlined in our proposal. So far, we have been very successful in generating and characterizing murine ES cell lines and have been able to produce three-dimensional thyroid neofollicles from these ES cells and show that these neofollicles express thyroglobulin. I 139

POSITION TITLE Baumritter Professor of Medicine, Mount Sinai School of Medicine, Chief, Endocrinology and Metabolism, James J Peters VAMC, NY, NY. DEGREE M.B.B.S. M.R.C.P. M.D. F.R.C.P.

MM/YY 1971 1974 1978 1986

FIELD OF STUDY Medicine/Surgery Medicine Endocrinology Medicine

would not anticipate any major methodological issues that would prevent successful completion of the proposed work and anticipate a paradigm shift that will usher in the time for thyroid cell therapy. B. Positions and Honors 1971-75 Medical Residency, Newcastle-upon-Tyne, United Kingdom. 1975-77 MRC Senior Research Associate, Endocrine Unit, University of Newcastle-upon-Tyne, UK. 1977-79 USPHS Visiting Fellow, ERRB, NICHD, NIH, Bethesda, MD. 1979-82 Assistant Professor of Medicine, Mount Sinai School of Medicine, New York, NY. 1982-86 Associate Professor of Medicine, Mount Sinai School of Medicine, New York, NY. 1986- Professor of Medicine, Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY. Honors: Medical Research Council Training Fellowship (1975-1977).

(1988).

USPHS International Fellowship (1977-1979). Irma T. Hirschl Career Scientist (1980-85). Member, American Society for Clinical Investigation

Florence and Theodore Baumritter Endowed Professor of Medicine (1990). Fellow, American College of Endocrinology (1996). Elected to the American Association of Physicians (1999). Editor in Chief of the “Thyroid” journal. (2001-2008) Ingbar Award of the American Thyroid Association (2002). President, American Thyroid Association (2009) Honorary Fellowship, University of Newcastle, UK (2012). C. Selected Peer-reviewed Publications (from more than 400 publications) Five most relevant to the current application: 1. Marians, R., Forrest, D., Ng, L., Graves, P., and Davies, T.F. The TSH receptor knock out mouse: characterization of thyroid hypofunction. Proceedings of the National Academy of Sciences 99:1577615781,2002. PMCID: PMC137792 2. Ando, T., Latif, R, Pritsker, A, Moran, T, Nagayama, Y. and Davies, T.F. A monoclonal thyroid stimulating antibody. Journal of Clinical Investigation 110:1667-1674, 2002. PMCID: PMC151640 3. Morshed, SA, Ando, T, Latif, R and Davies, TF Neutral autoantibodies to the TSH receptor are present In Graves’ disease and regulate selective signaling cascades. Endocrinology 151:5537-49, 2010. PMCID: PMC2954721 4. Ma R, Latif R, Davies TF. Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells. Thyroid. 2013 Apr;23(4):385-91. PMCID: PMC3610443

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5. Baliram, A, Sun, L, Cai, S, Li, J., Latif, R., Huber, AK, Blair, HC, Zaidi, M and Davies, TF. Absent TSH Signaling exacerbates the bone loss of hyperthyroidism. J. Clin. Invest. 2012 Oct 1;122(10):3737-41 PMCID: PMC3461920 Ten additional publications of importance to the field (in chronological order) 1. Tomer Y, Ban Y, Concepcion E, Barbesino G, Villanueva R, Greenberg DA, Davies TF. Common and unique susceptibility loci in Graves and Hashimoto diseases: Results of whole-genome screening in a data set of 102 multiplex families. Am J Hum Genet 2003; 73: 736-747. PMCID: PMC1180598 2. Lin, R-Y, Kubo, A., Keller, G.M., and Davies, T.F. Committing murine embryonic stem cells to differentiate into thyrocyte-like cells in vitro. Endocrinology 144:2644-2649, 2003. PMID:12746328 3. Abe, E, Marians, R.C., Yu, W., Wu,, X-B, Ando, T., Li, Y., Iqbal, J., Eldeiry, L., Rajendren, G., Blair, H.C., Davies, T.F., Zaidi, M. TSH is a negative regulator of skeletal remodeling. Cell, 115:151-162, 2003. PMID: 14567913 4. Ban Y, Davies TF, Greenberg DA, Concepcion ES, Osman R, Oashi T, Tomer Y. Arginine at position 74 of the HLA-DR beta 1 chain is associated with Graves’ disease. Genes and Immunity 5:203-208, 2004. PMID: 15029234 5. Latif, R. Ando, T. & Davies, T.F, Monomerization as a prerequisite for intramolecular cleavage and shedding of the thyrotropin receptor. Endocrinology 145:5580-5588, 2004. PMID: 15319351 6. Arufe, MC, Lu M, Kubo, A, Keller, G, Davies, TF, Lin R-Y. Directed differentiation of mouse embryonic stem cells into thyroid follicular cells. Endocrinology 147:3007-3015 (2006). PMID: 1592134

 

7. Latif, R and Davies, TF Lipid rafts as triage centers for multimeric and monomeric TSH receptor reg-ulation. Endocrinology 148:3164-3175 (2007). PMID: 17412816 8. Ma, Risheng, Latif, R., Davies, TF TSH-Independent induction of thyroid endoderm from embryonic stem cells by Activin A. Endocrinology 150:1970-5, 2009. PMCID: PMC2659285 9. Latif, R, Michalek, K, Latif, R., Davies, TF Subunit dimerization influences TSH receptor expression and

141

signaling. Molecular Endocrinology 24:2009-2018, 2010. PMCID: PMC2954635 10. Baliram R, Latif R, Berkowitz J, Frid S, Colaianni G, Sun L, Zaidi M, Davies TF. Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures. Proc Natl Acad Sci U S A. 2011 Sep 12. PMCID: PMC3182731

BIOGRAPHICAL SKETCH NAME Esplugues, Enric EDUCATION/TRAINING INSTITUTION AND LOCATION University of Barcelona University of Barcelona University of Barcelona (Postdoc Fellow) Yale University (Postdoc Fellow) Yale University (Associate Research Scientist) Mount Sinai School of Medicine (Assistant Prof.) A. Personal Statement For the last 15 years, my research has focused on identifying cellular and molecular mechanism that are important for the control of the immune system in humans and mice. I have studied cellular and molecular biological mechanisms relevant to cancer, autoimmunity, infections and different aspects of the immune system affecting their control during pathogenic processes. In my current appointment at Mount Sinai School of Medicine, Department of Medicine/Clinical Immunology Division and as a member of the Immunology Institute, I have recently established an independent research program around the topic Epigenetic Control of Inflammation. B. Positions and Honors 09.1992-10.1997 B.Sc., University of Barcelona 05.1998-10.2003 PhD student, Dept. of Animal Physiology, Immunology Unit. Barcelona, Spain (PI: Dr. Pilar Lauzurica) 11.2003-12.2004 Postdoctoral Fellow, Dept. of Animal Physiology, Immunology Unit. Barcelona, Spain (PI: Dr. Pilar Lauzurica)

POSITION TITLE Assistant Professor DEGREE B.S. Ph.D. -----

FIELD OF STUDY Biology (Biomedicine) Immunology/Cancer Immunology/Cancer Immunology/Genetics Immunology/Genetics Immunology/Genetics

02.2005-02.2008 Postdoctoral Fellow, Dept. of Immunobiology, School of Medicine. Yale University. New Haven, CT, USA. (PI: Dr. Richard A. Flavell) 03.2008-10.2011 Associate Research Scientist, Immunobiology Department, School of Medicine. Yale University. New Haven, CT, USA. 11.2011-Present Assistant Professor of Medicine, Clinical Immunology, Immunology Institute, Mount Sinai School of Medicine, New York, NY, USA Fellowships: 1998-2002 University of Barcelona Fellowship 2002-2003 UAM Fund Fellowship 2003-2004 Bosch and Gimpera Fund. Postdoctoral Fellowship 2005-2006 Spanish Ministry of Education Postdoctoral Fellowship 2006-2007 James Hudson Brown - Alexander B. Coxe Postdoctoral Fellowship 2007-2009 Howard Hughes Medical Institute Fellowship Awards:

142

MM/YY 10/1997 10/2003 11/2003 02/2005 03/2008 11/2011

Margalef Award 2005 (First edition) for the best paper published by a Ph.D. student of the University of Barcelona between 1999 and 2004 (5 year period). Patents: Immune regulation based on the targeting of early activation molecules Esplugues Artola, Enric; (Barcelona, ES) ; Sanchez-Madrid, Francisco; (Madrid, ES) ; Alonso, Carlos Martinez; (Madrid, ES) ; Madrid, David Sancho; (Madrid, ES) ; Rocamora, Pablo Engel; (Barcelona, ES) ; Ramos, Javier Vega; (Barcelona, ES) ; Gomez, Pilar Lauzurica; (Barcelona, ES) United States Patent Application: 20050002929 (January 6, 2005) Methods of treating viral hepatitis. Esplugues Artola, Enric; (Barcelona, ES) ; Sanchez-Madrid, Francisco; (Madrid, ES) ; Alonso, Carlos Martinez; (Madrid, ES) ; Madrid, David Sancho; (Madrid, ES) ; Rocamora, Pablo Engel; (Barcelona, ES) ; Ramos, Javier Vega; (Barcelona, ES) ; Gomez, Pilar Lauzurica; (Barcelona, ES) United States Patent Application: 20110081292 (April 7, 2011) Methods of treating cancer. Esplugues Artola, Enric; (Barcelona, ES) ; Sanchez-Madrid, Francisco; (Madrid, ES) ; Alonso, Carlos Martinez; (Madrid, ES) ; Madrid, David Sancho; (Madrid, ES) ; Rocamora, Pablo Engel; (Barcelona, ES) ; Ramos, Javier Vega; (Barcelona, ES) ; Gomez, Pilar Lauzurica; (Barcelona, ES) United States Patent Application: 20110165071 (July 7, 2011) C. Selected Peer-reviewed Publications 1. Oct-1 regulates IL-17 expression by directing interchromosomal associations in conjunction with CTCF in T cells. Kim LK, Esplugues E, ZorcaCE, Galjart NJ, Flavell RA Mol Cell. 2014 Mar 5.

143

2. Bcl6 expression specifies the T follicular helper cell program in vivo. Liu X, Yan X, Zhong B, Nurieva R, Wang A, Wang X, Martin-Orozco N, Wang Y, Chang SH, Esplugues E, Flavell RA, Tian Q, Dong C. J Exp Med. 2012 Sep 24;209(10):1841-52. Epub 2012 Sep 17. 3. Effector CD4+ T cell expression signatures and immunemediated disease associated genes. Zhang W, Ferguson J, Ng SM, Hui K, Goh G, Lin A, Esplugues E, Flavell RA, Abraham C, Zhao H, Cho JH PLoS One. 2012 June 8. 4. Enhanced anti-serpin antibody activity inhibits autoimmune inflammation in type-1 diabetes. Czyzyk J, Henegariu O, Preston-Hurlburt P, Badzizhar R, Fedorchuk C, Esplugues E, Bottomly K, Gorus FK, Herold K, Flavell RA J Immunol. 2012 June 15; 188(12):6319-27 5. Mir-33 regulates cell proliferation and cell cycle progression. Cirera-Salinas D, Pauta M, Allen RM, Salerno AG, Ramírez CM, Chamorro-Jorganes A,Wanschel AC, Lasuncion MA, Morales-Ruiz M, Suarez Y, Baldan A, Esplugues E, Fernández-Hernando C Cell Cycle. 2012 Mar 1;11(5) 6. Development of autoimmune diabetes in the absence of detectable IL-17A in a CD8-driven virally induced model. Van Belle TL*, Esplugues E*, Liao J, Juntti T, Flavell RA, von Herrath MG. J Immunol. 2011 Sep 15;187(6):2915-22 (*co-first authors) 7. Control of TH17 cells occurs in the Small Intestine. Esplugues E*#, Huber S*, Gagliani N, Hauser AE, Town T, Wan YY, O’Connor Jr. W, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA#. Nature. 2011 Jul 17; 475(7357):514-8. (*co-first authors, #co-directed the project) 8. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, Cirera-

9.

10.

11.

12.

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Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, Esplugues E, Fisher EA, Penalva LO, Moore KJ, Suárez Y, Lai E, FernándezHernando C. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9232-7 TH17 Cells Express Interleukin-10 Receptor and Are Controlled by Foxp3(-) and Foxp3(+) Regulatory CD4(+) T Cells in an Interleukin-10-Dependent Manner. Huber S*, Gagliani N*, Esplugues E*, O'Connor W Jr, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA. Immunity. 2011 Apr 22;34(4):554-65. (*co-first authors) CD69 targeting differentially affects the course of collageninduced arthritis. Sancho D, Gómez M, Martinez Del Hoyo G, Lamana A, Esplugues E, Lauzurica P, Martinez-A C, SánchezMadrid F. J Leukoc Biol. 2006 Dec;80(6):1233-41. The adaptor protein 3BP2 binds human CD244 and links this receptor to Vav signaling, ERK activation, and NK cell killing. Saborit-Villarroya I, Del Valle JM, Romero X, Esplugues E, Lauzurica P, Engel P, Martín M. J Immunol. 2005 Oct 1;175(7):4226-35. Induction of tumor NK-cell immunity by anti-CD69 antibody therapy. Esplugues E, Vega-Ramos J, Cartoixà D, Vazquez BN, Salaet I, Engel P, Lauzurica P. Blood. 2005 Jun 1;105(11):4399-406. CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collageninduced arthritis. Sancho D, Gómez M, Viedma F, Esplugues E, Gordón-Alonso M, García-López MA, de la Fuente H, Martínez-A C, Lauzurica P, Sánchez-Madrid F. J Clin Invest. 2003 Sep;112(6):872-82. Enhanced antitumor immunity in mice deficient in CD69. Esplugues E, Sancho D, Vega-Ramos J, Martínez C, Syrbe U,

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Hamann A, Engel P, Sánchez-Madrid F, Lauzurica P. J Exp Med. 2003 May 5;197(9):1093-106.

BIOGRAPHICAL SKETCH NAME Faith, Jeremiah James

EDUCATION/TRAINING INSTITUTION AND LOCATION Louisiana State University University of Wales, Swansea

DEGREE B.S.

YEAR(s) 1997-2001 1999

Boston University

Ph.D.

2003-2008

Washington University in St. Louis

Postdoc

2008-2011

A. Personal Statement My research focuses on data driven computational modeling of the microbiome with predictions that are followed-up experimentally with new or existing technologies. I have pursued aspects of this paradigm for the past 13 years, first as a scientific programmer studying evolutionary genomics, then as a graduate student developing network inference algorithms for large-scale bacterial microarray datasets, and most recently as a postdoctoral fellow and instructor in Dr. Jeffrey Gordon’s lab at Washington University in St. Louis where I applied statistical modeling and systems biology tools to the field of gut microbiome research. I have over 6 years of experience working in the microbiome field, developing experimental advances in gnotobiotics, anaerobic robotics for highthroughput microbial isolation and culturing, improvements in the scale and quality of 16S rRNA amplicon sequencing, and optimized rRNA depletion protocols and data processing pipelines for RNA-Seq metatranscriptomics of both the human and the mouse microbiota. 145

POSITION TITLE Assistant Professor of Medicine (Division of Clinical Immunology) Assistant Professor of Genetics and Genomics FIELD OF STUDY Zoology Study abroad/biology Bioinformatics and Systems Biology Human and mouse gut microbiome

My group’s current work is on modeling the interactions between diet, the microbiota, and host physiology. In addition, we are developing computational and experimental platforms to isolate and identify bacteria that modulate phenotypic changes in mice with an emphasis on the identification of microbes that perturb the immune system. B. Positions and Employment 2001-2002 Research Associate, Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 2002-2003 Scientific Programmer, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 2011-2012 Instructor, Department of Pathology and Immunology, Washington University, St. Louis, MO 2013- Assistant Professor, Department of Medicine, Mt Sinai School of Medicine, New York, NY 2013- Assistant Professor, Department of Genetics and Genomic Sciences, Mt Sinai School of Medicine, New York, NY

C. Selected Peer-reviewed publications (Selected from 21 peer-reviewed publications) 1. J.J. Faith*, P.P. Ahern*, V.K. Ridaura, J. Cheng, J.I. Gordon. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med. 2014 Jan 22; 6(220):220ra11. 2. V.K. Ridaura, J.J. Faith, F.E. Rey, J. Cheng, A.E. Duncan, A.L. Kau, N.W. Griffin, V. Lombard, B. Henrissat, J.R. Bain, M.J. Mehlbauer, O. Ilkayeva, C.F. Semenkovich, K. Funai, D.K. Hayashi, M.C. Martini, L.K. Ursell J.C. Clemente, W.V. Treuren, W.A. Walters, R. Knight, C.B. Newgard, A.C. Heath, J.I. Gordon. Cultured gut bacterial consortia from twins discordant for obesity modulate adiposity and metabolic phenotypes in gnotobiotic mice. Science 2013 Sept 6. PMCID: PMC3829625 3. J.J. Faith, J.L. Guruge, M. Charbonneau, S. Subramanian, H.S. Seedorf, A.L. Goodman, J.C. Clemente, R. Knight, A.C. Heath, R.L. Leibel, M. Rosenbaum, J.I. Gordon. The longterm stability of the human gut microbiota. Science. 2013 Jul 5. PMCID: PMC3791589 4. N.A. Bokulich, S. Subramanian, J.J. Faith, D. Gevers, J.I. Gordon, R. Knight, D.A. Mills, J.G. Caporaso. Qualityfiltering vastly improves diversity estimates from Illumina amplicon sequencing. Nat Methods. 2012 Dec 2. doi: 10.1038/nmeth.2276. PMCID: PMC3531572 5. C. Lozupone, K. Faust, J. Raes, J.J. Faith, D.N. Frank, J. Zaneveld, J.I. Gordon, R. Knight. Identifying genomic and metabolic features that can underlie early successional and opportunistic lifestyles of human gut symbionts. Genome Res. 2012 Jun 4. PMCID: PMC3460192 6. N.P. McNulty, T. Yatsunenko, A. Hsiao, J.J. Faith, B.D. Muegge, A.L. Goodman, B. Henrissat, R. Oozeer, S. CoolsPortier, G. Gobert, C. Chervaux, D. Knights, C.A. Lozupone,

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R. Knight, A.E. Duncan, J.R. Bain, M.J. Muehlbauer, C.B. Newgard, A.C. Heath, J.I. Gordon. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med. 2011 Oct 26;3(106):106ra106. PMCID: PMC3303609 J.J. Faith, N.P. McNulty, F.E. Rey, and J.I. Gordon. Predicting a Human Gut Microbiota’s Response to Diet in Gnotobiotic Mice. Science. 2011 May 19. PMCID: PMC3303606 A.L. Goodman, G.K. Kallstrom, J.J. Faith, A. Reyes, A. Moore, G. Dantas, and J.I. Gordon. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6252-7. PMCID: PMC3076821 J.J. Faith*, F.E. Rey*, D. O'Donnell, M. Karlsson, N.P. McNulty, G. Kallstrom, A.L. Goodman, and J.I. Gordon. Creating and characterizing communities of human gut microbes in gnotobiotic mice. ISME Journal. 2010. Sep;4(9):1094-8. Epub 2010 Jul 22. PMCID: PMC2927777 F.E. Rey*, J.J. Faith*, J. Bain, M.J. Muehlbauer, R.D. Stevens, C.B. Newgard, and J.I. Gordon. Dissecting the in vivo metabolic potential of two human gut acetogens. J Biol Chem. 2010 Jul 16;285(29):22082-90. Epub 2010 May 5. PMCID: PMC2903421 P.J. Turnbaugh, C. Quince, J.J. Faith, A.C. McHardy, T. Yatsunenko, F. Niazi, J. Affourtit, M. Egholm, B. Henrissat, R. Knight, and J.I. Gordon. Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc Natl Acad Sci U S A 2010 Apr 20;107(16):7503-8. Epub 2010 Apr 2. PMCID: PMC2867707 P.J. Turnbaugh, V.K. Ridaura, J.J. Faith, F.E. Rey, R. Knight, and J.I. Gordon. The effect of diet on the human gut

microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009 Nov 11;1(6):6ra14. PMCID: PMC2894525 13. J.J. Faith, M.E. Driscoll, V.A. Fusaro, E.J. Cosgrove, B. Hayete, F.S. Juhn, S.J. Schneider, and T.S. Gardner. Many Microbe Microarrays Database: uniformly normalized Affymetrix compendia with structured experimental metadata. Nucleic Acids Res. 2008 Jan;36 (Database issue):D866-70. PMCID: PMC2238822 14. J.J. Faith*, B.Hayete*, J.T. Thaden, I. Mogno, J. Wierzbowski,

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G. Cottarel, S. Kasif, J.J. Collins, and T.S. Gardner. LargeScale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles. PLoS Biol. 2007 Jan;5(1):e8. PMCID: PMC1764438 15. J.J. Faith and D.D. Pollock. Likelihood analysis of asymmetrical mutation bias gradients in vertebrate mitochondrial genomes. Genetics. 2003 Oct;165(2):735-45. PMCID: PMC1088294

BIOGRAPHICAL SKETCH NAME Furtado, Glaucia C. EDUCATION/TRAINING INSTITUTION AND LOCATION University of Santo Amaro, Sao Paulo, Brazil University of Sao Paulo, Sao Paulo, Brazil Advanced Postdoctoral Fellow, New York University A. Personal Statement: I have a long standing interest in autoimmune and inflammatory diseases. My early work showed an important role for IL-2 in Treg function and development. My current research focuses on mucosal inflammation, and lymphoid neogenesis in neonates and adults. B. Positions 1989-1990 Visiting Scientist, National Institutes of Health, Bethesda MD, USA. 1991-1992 Visiting Scientist Yale University School of Medicine, Connecticut CT, USA. 1993-1998 Researcher, Dept. Immunology, University of Sao Paulo SP, Brazil. 1996-1998 Consultant, Techinova-Inovacoes Cientificas, Sao Paulo SP. Brazil. 2003-2014 Assistant Professor, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA 2014Associate Professor, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Awards and Other Professional Activities: 148

POSITION TITLE Associate Professor DEGREE B.Sc. Ph.D. Post-Doc

MM/YY 1987 1993 1998-2003

FIELD OF STUDY Biology Immunology Immunology

1991–1994 Visiting Scientist fellow (CAPES), Brazil 1994–1996 Research Fellow – National Research Council (CNPq), Brazil 1998–2000 Fellow, Fundacao de Amparo a Ciencia do Estado de Sao Paulo (FAPESP), Brazil 2000–2003 Advanced Postdoctoral fellowship, National Multiple Sclerosis Society, New York, NY, USA C. Selected Publications: (Selected from 37 peer-reviewed publications) 1. Curotto de Lafaille MA, Muriglan S, Sunshine MJ, Lei Y, Kutchukhidze N, Furtado GC, Wensky AK, OlivaresVillagomez D, Lafaille JJ. Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes. J Exp Med 2001. 194:1349-1359. 2. Furtado GC, Olivares-Villagomez D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ. Regulatory T cells in spontaneous autoimmune encephalomyelitis. Immunol Rev 2001. 182:122-134.

3. Furtado, G.C., M.A. Curotto de Lafaille, N. Kutchukhidze, and J.J. Lafaille, Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med, 2002. 196:851-7. 4. Harroch, S., G.C. Furtado, W. Brueck, J. Rosenbluth, J. Lafaille, M. Chao, J.D. Buxbaum, and J. Schlessinger, A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions. Nat Genet, 2002. 32:411-4, PMID 12355066.3. 5. Lira, S.A., A.P. Martin, T. Marinkovic, and G.C. Furtado, Mechanisms regulating lymphocytic infiltration of the thyroid in murine models of thyroiditis. Crit Rev Immunol, 2005. 25:251-62. 6. Furtado, G.C., B. Pina, F. Tacke, S. Gaupp, N. van Rooijen, T.M. Moran, G.J. Randolph, R.M. Ransohoff, S.W. Chensue, C.S. Raine, and S.A. Lira, A novel model of demyelinating encephalomyelitis induced by monocytes and dendritic cells. J Immunol, 2006. 177:6871-9. 7. Lyddane C, Gajewska BU, Santos E, King PD, Furtado GC, Sadelain M. Cutting Edge: CD28 controls dominant regulatory T cell activity during active immunization. J Immunol 2006;176:3306-3310. 8. Marinkovic, T., A. Garin, Y. Yokota, Y.X. Fu, N.H. Ruddle, G.C. Furtado, and S.A. Lira, Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J Clin Invest, 2006. 116:2622-32. 9. Furtado, G.C., T. Marinkovic, A.P. Martin, A. Garin, B. Hoch, W. Hubner, B.K. Chen, E. Genden, M. Skobe, and S.A. Lira, Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc Natl Acad Sci U S A, 2007. 104:5026-31. 10. Marchesi F, Martin AP, Thirunarayanan N, Devany E, Mayer L, Grisotto MG, Furtado GC, Lira SA. CXCL13 expression in

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the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles. Mucosal Immunol 2009. 2:486-494. Shang L, Thirunarayanan N, Viejo-Borbolla A, Martin AP, Bogunovic M, Marchesi F, Unkeless JC, Ho Y, Furtado GC, Alcami A, Merad M, Mayer L, Lira SA. Expression of the chemokine binding protein M3 promotes marked changes in the accumulation of specific leukocytes subsets within the intestine. Gastroenterology 2009. 137:1006-1018. Viejo-Borbolla A, Martin AP, Muniz LR, Shang L, Marchesi F, Thirunarayanan N, Harpaz N, Garcia RA, Apostolaki M, Furtado GC, Mayer L, Kollias G, Alcami A, Lira SA. Attenuation of TNF-driven murine ileitis by intestinal expression of the viral immunomodulator CrmD. Mucosal Immunol 2010. 3:633-644. Bongers G, Maussang D, Muniz LR, Noriega VM, FraileRamos A, Barker N, Marchesi F, Thirunarayanan N, Vischer HF, Qin L, Mayer L, Harpaz N, Leurs R, Furtado GC, Clevers H, Tortorella D, Smit MJ, Lira SA. The cytomegalovirusencoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J Clin Invest 2010;120:39693978. (cover article) Muniz, L.R., M.E. Pacer, S.A. Lira, and G.C. Furtado, A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures. J Immunol, 2011. 187:828-34. Bongers G, Muniz LR, Pacer ME, Iuga AC, Thirunarayanan N, Slinger E, Smit MJ, Reddy EP, Mayer, Furtado GC, Harpaz N, Lira SA. A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans. Gastroenterology, 2012. 143:730-40. Nagao K, Kobayashi T, Moro K, Ohyama M, Adachi T, Kitashima DY, Ueha S, Horiuchi K, Tanizaki H, Kabashima K,

Kubo A, Cho YH, Clausen BE, Matsushima K, Suematsu M, Furtado GC, Lira SA, Farber JM, Udey MC, Amagai M. Stressinduced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat Immunol 2012. 13:744-752. 17. Lira SA, Furtado GC. The biology of chemokines and their receptors. Immunol. Res. 2012. 54:111-20. 18. Farache J, Koren I, Milo I, Gurevich I, Kim KW, Zigmond E, Furtado GC, Lira SA, Shakhar G. Luminal Bacteria Recruit CD103(+) Dendritic Cells into the Intestinal Epithelium to Sample Bacterial Antigens for Presentation. Immunity, 2013. 38:581-95.  

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19. Furtado GC, Pacer ME, Bongers G, Bénézech C, He Z, Chen L, Berin MC, Kollias G, Caamaño JH, Lira SA. TNFα-dependent development of lymphoid tissue in the absence of RORγt+ lymphoid tissue inducer cells. Mucosal Immunol. , 2014. 7:602-614. (cover article) 20. Bongers G, Pacer ME, Geraldino TH, Chen L, He Z, Hashimoto D, Furtado GC, Ochando J, Kelley KA, Clemente JC, Merad M, van Bakel H, Lira SA. Interplay of host microbiota, genetic perturbations, and inflammation promotes local development of intestinal neoplasms in mice. J Exp Med., 2014. 211:457-72. (cover article)

BIOGRAPHICAL SKETCH NAME Gnjatic, Sacha

EDUCATION/TRAINING INSTITUTION AND LOCATION University of Paris VI, France Ecole Normale Superieure, Paris, France Pasteur Institute and University of Paris VII University of Paris VII INSERM Cochin Inst. Paris Ludwig Institute MSKCC A. Personal Statement I am an immunologist who focuses on human immune responses to cancer in an antigen-specific manner, to define new targets for the development of cancer immunotherapies, ask how these immunotherapies work and why they may fail. My work on tumor antigens such as NY-ESO-1 has established the immunological basis for testing human cancer vaccines in over 40 clinical trials, opening a new field of cancer immunology based on clinical discovery rather than mouse models, with the goal to achieve protective integrated immune responses in the fight against cancer. I am also the Associate Director of the Immunomonitoring Core of Icahn School of Medicine at Mount Sinai Both my existing and future networks of collaborations with local and international academic and industrial partners will help guide and coordinate strategies for the design of correlative studies that aim to uncover the biological and immunological mechanisms underpinning clinical trial results so that one can learn from clinical successes as well as productive failures; to develop and validate biomarkers that can serve as predictors of 151

POSITION TITLE Associate Professor; Division of Oncology and Hematology; Tisch Cancer Institute; Immunology Institute; Icahn School of Medicine at Mount Sinai DEGREE BSc equiv. MSc equiv. Masters/Dipl PhD Post-Doc

YEAR(s) 06/1994 06/1995 06/1995 07/1998 1998–2001

FIELD OF STUDY Biology/Biochemistry Biology/Biochemistry Immunology Immunology Tumor Immunology

response; to guide the choice of immunological agent(s) tested and to shape questions being addressed by clinical trials. My work has resulted in 115 publications in high impact peerreviewed journals (most have themselves been cited between 20-500 times by other authors) and nearly 10 patents. My work has also been presented in over 90 international meetings related to immunology and/or cancer, open to both scientists and clinicians. I trained and taught immunological concepts to 8 post-doctoral fellows and 13 technicians. My laboratory has also served as reference for harmonized immunomonitoring for the Cancer Vaccine Collaborative, which has led to the adoption of new standards in serology by other labs. I bring unique expertise in both humoral and cellular immunology against human cancer antigens. My past and proposed research projects are highly relevant to cancer immunology and immunotherapy, bridging laboratory and clinical discovery. I am highly collaborative, and able to foster environment conducive to clinically relevant advances in the field of cancer immunotherapy. As PI or co-Investigator, I have experience with obtaining and renewing grants, from both

private philanthropic and public funding sources. In addition, I successfully administered projects (e.g. staffing, research protections, budget), collaborated with other researchers, and produced many peer-reviewed publications from each project. As a result of these previous experiences, I am aware of the importance of frequent communication among project members and of constructing a realistic research plan, timeline, and budget. In summary, I have a demonstrated record of successful and productive research projects in an area of high relevance for cancer immunotherapy. B. Positions and Honors Positions 2001–2007 Assistant Member, Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 2001–2012 Visiting Investigator, Sloan-Kettering Institute for Cancer Research, New York, NY 2007–2012 Director of Immunological Monitoring, Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 2007–2012 Associate Member, Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 2010 Adjunct Associate Professor, Roswell Park Cancer Institute, Buffalo, NY 2010 Invited Researcher, Immunology Frontier Research Center, University of Osaka, Japan 2013–present Associate Director of Immunomonitoring Core, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 2013–present Associate Professor (Hematology/Oncology, Immunology), Tisch Cancer Institute,

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Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY Other Experiences and Professional Memberships 1991–present Alumnus of University College London – United Kingdom 1995-present Alumnus of the Pasteur Institute – France 2011-present Associate Editor – Frontiers in Immunology 2011-present Correlative Science Committee Member of the NCI Cancer Immunotherapy Trials Network 2011-present Scientific Advisory Board Member of the Broad Institute’s Cancer Vaccine Project 2012-2013 Contributing Editor – Cancer Immunity 2013-present Editorial Board Member – Cancer Immunology Research 2013-present Scientific Advisory Board Member of Boehringer-Ingelheim Cancer Vaccine 2013-present Scientific Advisory Board Member (pending) of Janssen R&D 2013-present Member of American Association for Cancer Research (AACR) 2013-present Member of Society for Immunotherapy of Cancer (SITC) C. Selected peer-reviewed publications (from a total of 115 peer-reviewed publications) 1. Gnjatic S, Nagata Y, Jäger E, Stockert E, Shankara S, Roberts BL, Mazzara GP, Lee SY, Dunbar PR, Dupont B, Cerundolo V, Ritter G, Chen YT, Knuth A, Old LJ. Strategy for monitoring T cell responses to NY-ESO-1 in patients with any HLA class I allele. Proc Natl Acad Sci U S A. 2000;97:10917-10922. PMC27124 2. Gnjatic S, Atanackovic D, Matsuo M, Jäger E, Lee SY, Valmori D, Chen YT, Ritter G, Knuth A, Old LJ. Cross-presentation of

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4.

5.

6.

7.

8.

HLA class I epitopes from exogenous NY-ESO-1 polypeptides by nonprofessional APCs. J Immunol. 2003;170:1191-1196. Gnjatic S, Atanackovic D, Jäger E, Matsuo M, Selvakumar A, Altorki NK, Maki RG, Dupont B, Ritter G, Chen YT, Knuth A, Old LJ. Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: Correlation with antibody responses. Proc Natl Acad Sci U S A. 2003;100:8862-8867. PMC166404 Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E, Santiago D, Ferrara CA, Matsuo M, Selvakumar A, Dupont B, Chen YT, Hoffman EW, Ritter G, Old LJ, Gnjatic S. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol. 2004;172:3289-3296. Nishikawa H, Qian F, Tsuji T, Ritter G, Old LJ, Odunsi* K, Gnjatic* S. Influence of CD4+CD25+ regulatory T cells on low/high-avidity CD4+ T cells following peptide vaccination. J Immunol. 2006;176:6340-6346. Nishikawa H, Sato E, Briones G, Chen LM, Matsuo M, Nagata Y, Ritter G, Jäger E, Nomura H, Kondo S, Tawara I, Kato T, Shiku H, Old LJ, Galan JE, Gnjatic S. In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines. J Clin Invest. 2006;116:19461954. PMC1481660 Nishikawa H, Tsuji T, Jäger E, Briones G, Ritter G, Old LJ, Galan JE, Shiku H, Gnjatic S. Induction of regulatory T cellresistant helper CD4+ T cells by bacterial vector. Blood. 2007;111:1404-1412. Atanackovic D, Altorki NK, Cao Y, Ritter E, Ferrara CA, Ritter G, Hoffman EW, Bokemeyer C, Old LJ, Gnjatic S. Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending

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on priming. Proc Natl Acad Sci U S A. 2008;105:1650-1655. PMC2234199 Gnjatic* S, Yuan* J, Li H, Powel S, Gallardo HF, Ritter E, Ku GY, Jungbluth AA, Segal NH, Rasalan TS, Manukian G, Xu Y, Roman RA, Terzulli SL, Heywood M, Pogoriler E, Ritter G, Old LJ, Allison JP, Wolchok JD. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci U S A. 2008;105:20410-20415. PMC2629307 Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358:2698-2703. PMC3277288 Tsuji T, Altorki NK, Ritter G, Old LJ, Gnjatic S. Characterization of preexisting MAGE-A3-specific CD4+ T cells in cancer patients and healthy individuals and their activation by protein vaccination. J Immunol. 2009;183:48008. Gnjatic S, Ritter E, Büchler MW, Giese NA, Brors B, Frei C, Murray A, Halama N, Zörnig I, Chen YT, Andrews C, Ritter G, Old LJ, Odunsi K, Jäger D. Seromic profiling of ovarian and pancreatic cancer. Proc Natl Acad Sci U S A. 2010;107:508893. PMC2840360 Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, Xu Y, Pogoriler E, Terzulli SL, Kuk D, Panageas KS, Ritter G, Sznol M, Halaban R, Jungbluth AA, Allison JP, Old LJ, Wolchok* JD, Gnjatic* S. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci U S A. 2011;108:16723-8. PMC3189057

14. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JD. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925-31. PMC3345206 15. Sabbatini PJ, Tsuji T, Ferran L, Ritter E, Sedrak C, Tuballes K, Jungbluth AA, Ritter G, Aghajanian C, Bell-McGuinn K,

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Hensley ML, Konner J, Tew W, Spriggs DR, Hoffman EW, Venhaus R, Pan L, Salazar AM, Magid Diefenbach C, Old L, Gnjatic S. Phase I trial of overlapping long peptides from a tumor self-antigen and Poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients. Clin Cancer Res. 2012;18:6497-508. 16. Gnjatic S, Bhardwaj N. Antigen depots: T cell traps? Nat Med. 2013;19:397-8. * Equal contribution

 

BIOGRAPHICAL SKETCH NAME Gulko, Percio S. INSTITUTION AND LOCATION Universidade Federal do Rio Grande do Sul (UFRGS), Brazil Medical College of Georgia, Augusta, GA National Institutes of Health, Bethesda, MD A. Personal Statement I am a board-certified rheumatologist, the Chief of Rheumatology and a Professor of Medicine at the Icahn School of Medicine at Mount Sinai. My goal is to identify genes implicated in the regulation of severity and joint damage in rheumatoid arthritis (RA), and to generate new targets and for the development of more effective therapies. My laboratory has been using a) rodent models of autoimmune arthritis to identify and characterize genes involved in the regulation of arthritis severity and joint damage, and b) synovial tissues and cells (fibroblast-like synoviocytes, FLS) from patients with RA to identify genes implicated in cell invasion and articular damage. During the past five years I have been a Principal Investigator in three different NIH R01 grants, all related to RA pathogenesis, and all lead to publications in highly respected peer-reviewed journals. I currently lead the Division of Rheumatology and a growing laboratory at Mount Sinai and have established successful and productive collaborations with other research groups. We have identified several severity and joint damage non-MHC loci. We have also discovered that these arthritis loci operate via the regulation of important phenotypes in disease pathogenesis such as the invasive properties of FLS. We have 155

POSITION TITLE Professor DEGREE

MM/YY

FIELD OF STUDY

M.D.

1987

Medicine

Residency Fellowship

1995 1997

Internal Medicine Rheumatology

identified new regulators of FLS invasion and new role for nuclear receptors and ion channels in the regulation of rheumatoid arthritis synovial fibroblast biology and their invasive behavior. In summary, my experience and interests, as well as my strong commitment with translating the results of my research to improving human health are directly relevant to the goals of the MSSM Immunology Institute. B. Positions and Honors Positions and Employment 1987-1988 Intern in Internal Medicine, UFRGS, Porto Alegre, Brazil 1988-1990 Rheumatology Fellow, UFRGS, Porto Alegre, Brazil 1991-1992 Rheumatology Fellow, Univ. Alabama Birmingham, Birmingham 1992-1995 Resident in Internal Medicine, Medical College of Georgia, Augusta, Georgia 1995-1997 Fellow in Rheumatology, NIAMS, National Institutes of Health, Bethesda, MD 1997-1999 Post-Doctoral Scientist, Columbia University, New York, NY 1999-2001 Assistant Professor, Medicine/Pediatrics, Columbia University, New York, NY

2001-2007 Associate Investigator, Feinstein Institute for Medical Research, Manhasset, NY 2001-2014 Director, Laboratory of Experimental Rheumatology, Feinstein Institute for Medical Research, Center for Genomics and Human Genetics 2002-2005 Assistant Professor, New York University School of Medicine, New York, NY 2005-2010 Associate Professor, New York University School of Medicine, New York, NY 2002-2014 Attending Physician, North Shore University Hospital, Manhasset, NY 2002-2007 Associate Prof., Elmezzi Graduate School of Mol. Medicine at NSLIJ, Manhasset, NY 2007-2014 Investigator, Feinstein Institute for Medical Research, Manhasset, NY 2007-2014 Professor, Elmezzi Graduate School of Molecular Medicine at NSLIJ, Manhasset, NY 2009-2014 Professor of Molecular Medicine, Hofstra University School of Medicine, NY 2014-present Professor of Medicine and Chief, Division of Rheumatology, Icahn School of Medicine at Mount Sinai; faculty at the Mount Sinai Graduate School and at the Mount Sinai Immunology Institite. Other Experience and Professional Memberships Professional Organizations and Societies Brazilian Society of Rheumatology. American College of Rheumatology. Board and Certification 1990 Certified, Brazilian Board of Rheumatology, Brazil (Brazilian Rheumatology Association). 1995 Certified, American Board of Internal Medicine. 2000 Certified, American Board of Internal Medicine (Rheumatology).

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Awards 1991 Research Award, Birmingham Chapter of the Lupus Foundation of America. 1991 Research Award, Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia). 1997 Research Award, American Autoimmune-related Diseases Association. C. Selected Peer-Reviewed Publications (from a total of 65) Most relevant to the current application 1. Brenner M, Laragione T, Mello A, Gulko PS. Cia25 on rat chromosome 12 regulates severity of autoimmune arthritis induced with pristane and collagen. Ann. Rheum. Dis. 2007, 66:952-957. PMCID: PMC1955106. 2. Chan A, Akhtar M, Brenner M, Zheng Y, Gulko PS, Symons M. The GTPase Rac Regulates the Proliferation and Invasion of Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients. Mol. Med. 2007, 13:297-304. PMCID: PMC1906689. 3. Laragione T, Brenner M, Li W, Gulko PS. Cia5d regulates a new fibroblast-like synoviocyte invasion-associated gene expression signature. Arthritis Res. Ther. 2008, 10:R92. PMCID: PMC2575606. 4. Laragione T, Brenner M, Mello A, Symons M, Gulko PS. The arthritis severity locus Cia5d is a novel genetic regulator of the invasive properties of synovial fibroblasts Arthritis Rheum. 2008, 58:2296-306. PMCID: PMC2714698. 5. Laragione T, Gulko PS. mTOR Regulates the Invasive Properties of Synovial Fibroblasts in Rheumatoid Arthritis. Mol Med. 2010 Sep-Oct;16(9-10):352-8. Epub 2010 May 27. PMCID: PMC2935948. 6. Laragione T, Brenner M, Sherry B, Gulko PS. CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in

 

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rheumatoid arthritis. Arthritis Rheum. 2011 Nov;63(11):327483. PMCID: PMC3205193. Laragione T, Shah A, Gulko PS. The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion And Morphology. Mol Med. 2011 Nov 2. doi: 10.2119/molmed.2011.00410. [Epub ahead of print]. PMCID: PMC3320133. Brenner M, Linge CP, Li W, Gulko PS. Increased synovial expression of nuclear receptors correlates with arthritis protection: A possible novel genetically-regulated homeostatic mechanism. Arthritis Rheum. 2011 Jun 23. doi: 10.1002/art.30507. [Epub ahead of print]. PMCID: PMC3183331. Hu X, Laragione T, Sun L, Koshy S, Jones KR, Ismailov II, Yotnda P, Horrigan FT, Gulko PS, Beeton C. KCa1.1 potassium channels regulate key pro-inflammatory and invasive properties of fibroblast-like synoviocytes in rheumatoid arthritis. J Biol Chem. 2012 Feb 3;287(6):4014-22. PMCID: PMC3281680. Laragione T, Gulko PS. Liver X Receptor (LXR) regulates rheumatoid arthritis fibroblast-like synoviocytes invasiveness, MMP-2 activation, IL-6 and CXCL10. Mol Med. 2012 Sep 7;18:1009-17 Liu Z, Bethunaickan R, Sahu R, Brenner M, Laragione M, Gulko PS, Davidson A. The multiple chemokine-binding Bovine Herpesvirus 1 Glycoprotein G (BHV1gG) inhibits polymorphonuclear cell but not monocyte migration into inflammatory sites. Mol Med. 2013 Aug 21. doi: 10.2119/molmed.2013.00339. [Epub ahead of print] Laragione T, Cheng KF, Tanner MR, He M, Beeton C, Al-Abed Y, Gulko PS. The Cation Channel Trpv2 Is A New Suppressor Of Arthritis Severity, Joint Damage And Synovial Fibroblast Invasion. Submitted April 2014.

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Additional recent publications of importance to the field 1. Gulko PS, Seki T, Winchester RJ. Fibroblast synoviocytes: their intrinsic and modified phenotypes and their potential role in the pathogenesis of rheumatoid arthritis. In Rheumatoid arthritis: the new frontiers in pathogenesis and treatment (first edition). Firestein G, Panayi G, Wollheim F. (editors), Oxford Press, New York, pp. 113-135, 2000. 2. Meng HC, Griffiths MM, Remmers EF, Kawahito Y, Li W, Neisa R, Cannon GW, Wilder RL, Gulko PS. Identification Of Two Novel Female-Specific Non-MHC Loci Regulating Collagen-Induced Arthritis Severity And Chronicity, And Evidence For Epistasis. Arthritis Rheum. 2004, 50:26952705. 3. Brenner M, Meng HC, Yarlett NC, Griffiths MM, Remmers EF, Wilder RL, Gulko PS. The non-MHC quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation and joint damage. Arthritis Rheum. 2005, 52:322-32. 4. Brenner M, Meng HC, Yarlett NC, Joe B, Griffiths MM, Remmers EF, Wilder RL, Gulko PS. The non-MHC quantitative trait locus Cia5 contains three major arthritis genes that differentially regulate disease severity, pannus formation and joint damage in collagen- and pristaneinduced arthritis. J. Immunol. 2005, 174:7894-902. 5. Brenner M, Laragione T, Yarlett NC, Li W, Mello A, Gulko PS. Cia27 is a novel non-MHC arthritis severity locus on rat hromosome 10 syntenic to the rheumatoid arthritis 17q22q25 locus. Genes Immun. 2006, 7:335-341. 6. Laragione, T, Yarlett NC, Brenner M, Mello A, Sherry B, Miller EJ, Metz CN, Gulko PS. The arthritis severity quantitative trait loci (QTL) Cia4 and Cia6 regulate neutrophil migration into inflammatory sites and levels of TNFα and nitric oxide. J. Immunol. 2007, 178:2344-2351.

7. Brenner M, Laragione T, Yarlett NC, Gulko PS. Genetic regulation of T regulatory, CD4, and CD8 cell numbers by the arthritis severity loci Cia5a, Cia5d and the MHC in the rat. Mol. Med. 2007, 13:277-287. PMCID: PMC1936230. 8. Gulko PS. Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis. Genes Immun. 2007, 8:523-531. 9. Johannesson M, Lopez-Aumatell R, Stridh P, Diez M, Tuncel J, Blázquez G, Martinez-Membrives E, Cañete T, VicensCosta E, Graham D, Copley RR, Hernandez-Pliego P, Beyeen AD, Ockinger J, Fernández-Santamaría C, Gulko PS, Brenner M, Tobeña A, Guitart-Masip M, Giménez-Llort L, Dominiczak A, Holmdahl R, Gauguier D, Olsson T, Mott R, Valdar W, Redei EE, Fernández-Teruel A, Flint J. A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock. Genome Res. 2009, 19:150-8. PMCID: PMC2612958. 10. Zhang Y, Lin X, Koga K, Takahashi K, Linge HM, Mello A, Laragione T, Gulko PS, Miller EJ. Strain Differences in Alveolar Neutrophil Infiltration and Macrophage Phenotypes in an Acute Lung Inflammation Model. Mol Med. 2011 Apr 28. doi: 10.2119/molmed.2010.00064. [Epub ahead of print]. PMCID: PMC3146623. 11. Jenkins E, Brenner M, Laragione T, Gulko PS. Synovial expression of Th17-related and cancer-associated genes is regulated by the arthritis severity locus Cia10. Genes Immun. 2011 Nov 3. doi: 10.1038/gene.2011.73. [Epub ahead of print]. PMCID: PMC3339715. 12. Brenner M, Laragione T, Shah A, Mello A, Remmers EF, Wilder RL, Gulko PS. Identification of two new arthritis severity loci that regulate levels of autoantibodies, IL-1β and joint damage. Arthritis Rheum. 2011 Nov 10. doi:

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10.1002/art.33468. [Epub ahead of print]. PMCID: PMC3288617. Brenner M, Gulko PS. The arthritis severity locus Cia5a regulates the expression of inflammatory mediators including Syk pathway genes and proteases in pristaneinduced arthritis. BMC Genomics. 2012 Dec 19;13(1):710. [Epub ahead of print]. Brenner M, Laragione T, Gulko PS. The arthritis severity locus Cia4 is an early regulator of IL-6, IL-1β, and NFκB activators’ expression in pristane-induced arthritis. Physiol Genomics. 2013 Jul 2;45(13):552-64. doi: 10.1152/physiolgenomics.00029.2013. Epub 2013 May 21. Guo X, Brenner M, Zhang X, Laragione T, Tai S, Li Y, Bu J, Yin Y, Shah AA, Kwan K, Li Y, Jun W, Gulko PS. Whole-Genome Sequences of DA and F344 Rats with Different Susceptibilities to Arthritis, Autoimmunity, Inflammation and Cancer. Genetics. 2013 Aug;194(4):1017-28. doi: 10.1534/genetics.113.153049. Epub 2013 May 20. Brenner B, Laragione T, Gulko PS. Analyses of synovial tissues from arthritic and protected congenic rat strains reveals a new core set of genes associated with disease severity. Physiol Genomics 2013 Nov 15;45(22):1109-22. doi: 10.1152/physiolgenomics.00108.2013. Epub 2013 Sep 17.

BIOGRAPHICAL SKETCH NAME Guttman-Yassky, Emma EDUCATION/TRAINING INSTITUTION AND LOCATION Sapir Medical Center, Meir, Kfar Saba, Israel Sackler School of Medicine, Tel-Aviv, Israel Technion-Israel Institute of Technology, Haifa, Israel Rambam Medical Center, Haifa, Israel Memorial Sloan Kettering Cancer Center, New York, NY Bar-Ilan University, Ramat Gan, Israel Weill Cornell Medical College, New York, NY The Rockefeller University, New York, NY A. Personal Statement My research made paradigm-shifting discoveries on the immunologic basis of atopic dermatitis/eczema (AD) in humans, enriching the understanding of the pathophysiology of this common disorder and opening the door to new therapeutic discoveries. I have developed the only comprehensive molecular maps of AD, defining skin differentiation and immune-circuits characterizing this disease. Although linked to both immune and barrier abnormalities, AD’s primary pathogenesis has not been elucidated. This incomplete mechanistic understanding has resulted in lack of effective targeted therapeutics. I am the first to identify in humans a distinct population of T-cells that independently produce IL-22, without co-producing IL-17 (as in mice), framing the concept that in humans Th22 T-cells are distinct from Th17 T-cells. My research revealed that this novel 159

POSITION TITLE Associate Professor (Academic Track), Icahn School of Medicine at Mount Sinai Medical Center, NY DEGREE Internship MD

MM/YY 03/98 06/98

FIELD OF STUDY Internal Medicine Medicine

MSc

10/03

Virology

Resident

12/04

Dermatology

Intern

6/08

Internal Medicine

PhD Resident

12/10 06/11

Fellow

07/07

Virology Dermatology Atopic Dermatitis Psoriasis

Th22/IL-22 pathway is highly activated in AD lesions, correlating with disease severity, and suggesting a pathogenic role for this axis. My findings conceptualized AD as a Th2/Th22-polarized disease, expanding the prevailing view of AD as a Th2-skewed disease. I associated IL-22 as a potential link between the barrier and immune abnormalities characterizing AD, showing that it inhibits differentiation proteins and induces epidermal hyperplasia, both major characteristics of AD, thus paving the path for potential new therapeutics. I have also designed a clinical trial which has been funded recently by the NIH, utilizing an anti-IL-22 antibody, the first to explore the biological effects of blocking IL-22 on AD disease activity and associated skin pathology. I have also established the reversibility of the AD phenotype and defined a series of

disease- and therapeutic response-biomarkers that will allow testing of targeted therapeutics. Positions and Employment 1997-1998 Rotating Internship, Sapir Medical Center, Meir, Kfar Saba, Israel 2000-2004 Resident in Dermatology, Department of Dermatology, Rambam Medical Center, Haifa, Israel 2005-2007 Instructor in Clinical Investigation, Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY 2007-2011 Associate Fellow, Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY 2008-2011 Dermatology Resident, Department of Dermatology, Weill Cornell Medical College, New York, NY 2011-present Associate Professor of Dermatology and Immunology, Departments of Dermatology and Immunology, Mount Sinai School of Medicine, New York, NY 2011-present Adjunct Associate Professor, the laboratory for Investigative dermatology, The Rockefeller University Professional Memberships 2005 – present Israeli Dermatological Society 2006 – present American Academy of Dermatology 2010 - present Women Dermatology Society 2011 - present Society for Investigative dermatology 2011 – present American Contact Dermatitis Society 2012- present Federation of Clinical Immunological Societies (FOCIS) 2014/1Advisory Board Member, National Eczema Association Honors 2001 2001 Prize for best tutor of medical students, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology

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2001 Travel Award, European society of Dermatopathology and Dermatology Meeting, Antalia, Turkey 2004 Everett Fox Award, best research at the Residents & Fellows Symposium at the 62nd Annual Meeting of the American Academy of Dermatology (AAD), Washington, DC 2004 Best Research Award, 28th national scientific convention of the Israeli Dermatological Society, Eilat, Israel 2004 Special prize of excellency in teaching dermatology to medical students, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and the Department of Dermatology, Rambam Medical Center 2004 Travel award of the International committee of the AAD meeting, Washington DC. 2005 “Best Resident Performance” Award after the Israeli Dermatological boards 2008 Montagna Symposium Travel Award, Montagna Symposium on Inflammatory Skin Diseases, Portland, Oregon 2009 3rd place Award, NY Academy of Medicine research competition for dermatology residents 2011 Young Investigator Award of the American Academy of Dermatology, New Orleans, LA 2011 Dermatology Foundation Physician-Scientist Career Development Award Selected Peer-reviewed Publications (of a total of 45 peerreviewed publications) 1. Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Whynot J, Novitskaya I, Cardinale I, Haider A, Khatcherian A, Carucci JA, Bergman R, Krueger JG. Major differences in the inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis. J Allergy Clin Immunol 2007; 19(5): 1210-7. PMID: 17472813. 2. Guttman-Yassky E, Vugmeyster Y, Lowes MA, Chamian F, Kikuchi T, Kagen M, Gilleaudeau P, Lee E, Hunte B, Howell K,

Dummer W, Bodary SC, Krueger JG. Blockade of CD11a by Efalizumab in Psoriasis Patients Induces a Unique State of TCell Hyporesponsiveness. J Invest Dermatol 2008; 128(5):1182-91. PMID: 18239614, PMCID – Journal in Process 3. Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I, Nograles KE, Khatcherian A, Novitskaya I, Carucci JA, Bergman R, and Krueger JG. Low expression of the IL-23/Th17 pathway in Atopic dermatitis compared to Psoriasis. J Immunol. 2008; 181(10):7420-7. PMID: 18981165, PMCID: PMC3470474 4. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E. IL-22 producing “T22” T-cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing Th17 T-cells. J Allergy Clin Immunol. 2009; 123(6): 1244-52. PMID: 191439349, PMCID – Journal in Process 5. Zaba LC, Suárez-Fariñas M, Fuentes-Duculan J, Nograles KE, Guttman-Yassky E, Cardinale I, Lowes MA, Krueger JG. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol. 2009 Nov;124(5):1022-10.e1395. PMID: 19895991, PMCID: PMC2852188. 6. Guttman-Yassky E, Suárez-Fariñas M, Chiricozz A, Nograles KE, Shemer A, Fuentes-Duculan J, Cardinale I, Peng L, Bergman R, Bowcock AM, Krueger JG. Broad defects in epidermal cornification in atopic dermatitis (AD) identified through genomic analysis. J Allergy Clin Immunol 2009 Dec; 124:1235-1244. PMID: 20004782, PMCID – Journal in Process. 7. Nograles KE, Suarez-Farinas M, Shemer A, Fuentes-Duculan J, Chiricozzi A, Cardinale I, Zaba LC, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E. Atopic Dermatitis (AD) keratinocytes exhibit normal Th17 cytokine

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responses. J Allergy Clin Immunol 2010. March 2010;125(3):744-6. PMID: 20226306, NIHMS167482. 8. Guttman-Yassky E, Mita A, De Jonge M, Matthews L, McCarthy S, Iwata KK, Rowinsky EK, Krueger JG..Characterization of the cutaneous pathology in nonsmall cell lung cancer (NSCLC) patients treated with the EGFR Tyrosine Kinase Inhibitor Erlotinib. Eur J Cancer. 2010 July;46: 2010-9. PMID: 20621734, PMCID – Journal in Process. 9. Chiricozzi A*, Guttman-Yassky E*, Suarez-Farinas M, Nograles KE, Tian S, Chimenti S, Krueger JG. Integrative responses to IL-17 and TNF-alfa in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 2011 Mar;131(3):677-87. PMID: 21085185, PMCID – Journal in Process. 10. Suarez-Farinas M, Tintle SJ, Shemer A, Chiricozzi A, Nograles KE, Cardinale I, Shenghui Duan, Bowcok AM, Krueger JG, Guttman-Yassky E. Non-lesional atopic dermatitis (AD) skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol 2011 April.127(4):954-64.e1-4. PMID: 21388663, PMCID: PMC3128983. 11. Fujita H, Shemer A, Suarez-Farinas M, Tintle SJ, Cardinale I, Fuentes-Duculan J, Novitskaya I, Carucci JA, Krueger JG, Guttman-Yassky E. Lesional dendritic cells in atopic dermatitis and psoriasis exhibit parallel T-cell polarizing ability. J Allergy Clin Immunol 2011. 2011 Sep;128(3):57482.e1-12. PMID: 21704361, PMCID – Journal in Process. 12. Tintle SJ, Shemer A, Suarez-Farinas M, Fujita H, Cardinale I, Shenghui Duan, Bowcok AM, Krueger JG, Guttman-Yassky E. Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers of therapeutic response. J Allergy Clin Immunol 2011. 2011 Sep;128(3):583-93.e1-4. PMID: 21762976, PMCID: PMC3448950.

13. Gittler JK, Shemer A, Suarez-Farinas M, Suarez-Farinas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQF, Mitsui H, Cardinale I, de Guzman Strong C, Krueger JG, GuttmanYassky E. Progressive activation of Th2/Th22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012 Aug 27. PMID: 22951056, NIHMS484572. 14. Gittler JK, Krueger JG, Guttman-Yassky E. Atopic Dermatitis has intrinsic barrier and immune abnormalities: implications for contact dermatitis. J Allergy Clin Immunol. 2012 Aug 28. [Epub ahead of print]. PMID: 22939651, PMCID – Journal in Process. 15. Suárez-Fariñas M, Gittler JK, Shemer A, Cardinale I, Krueger JG, Guttman-Yassky E. Residual genomic signature of atopic dermatitis despite clinical resolution with narrow-band UVB. J Allergy Clin Immunol 2013; 13(4):549-61.

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16. Guttman-Yassky E, Dhingra N, Leung DY. Biologics in Atopic Dermatitis. Expert Opin Biol Ther. 2013 Apr;13(4):549-61. 17. Suárez-Fariñas M, Dhingra N,, Gittler JK, Shemer A, Cardinale I, de Guzman Strong C, Krueger JG, Guttman-Yassky E. Intrinsic atopic dermatitis (AD) shows similar Th2 and higher Th17 immune activation compared to extrinsic AD. J Allergy Clin Immunol 2013 Aug;132(2):361-70. PMID: 23777851 18. Dhingra N, Suárez-Fariñas M, Fuentes-Duculan J, Gittler JK, Shemer A, Raz A, Fischetti VA, Krueger JG, Guttman-Yassky E. Attenuated neutrophil axis in atopic dermatitis (AD) compared with psoriasis reflects Th17 pathway differences between the two diseases. J Allergy Clin Immunol 2013 Aug;132(2):498-501.

BIOGRAPHICAL SKETCH NAME Heeger, Peter S. EDUCATION/TRAINING

POSITION TITLE Professor of Medicine

INSTITUTION AND LOCATION

DEGREE

YEAR(s)

FIELD OF STUDY

University of Pennsylvania University of Pennsylvania

BA MD

1980 1984

Biology Medicine

A. Personal Statement I am a Professor of Medicine and Immunology and Director of the Translational Transplant Research Center at the Icahn School of Medicine at Mount Sinai. I spend ~85% of my time performing and or overseeing research efforts in transplantation. I have >18 years of continuous NIH funding including >14 years of R01 funding and ~110 publications on the basic and translational mechanisms underlying transplant rejection and tolerance in mouse models and in human transplant recipients. I am a former K08 recipient, I am PI of an NIH T32 grant for postdocs in transplantation biology, and I have successfully supported more than a dozen K recipients. I have the expertise to train MD and PhD trainees as part of this T32. B. Professional Positions 1984-1987 Intern/Resident, Internal Medicine, Temple University Hospital (Sidney Cohen, M. D., Chairman), Philadelphia, PA 1989-1992 Research Fellow, Dr. Eric G. Neilson's Laboratory , Renal-Electrolyte Section, Department of Medicine, University of Pennsylvania, Philadelphia, PA 1988-1989 Clinical Fellow, Renal-Electrolyte Section , Hospital of the University of Pennsylvania, Philadelphia, PA

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1993-present Staff Physician, Cleveland VA Medical center, Cleveland OH Secondary appointment, Department of Pathology, CWRU, Michael Lamm, Chairman 1993-2000 Assistant Professor, Division of Nephrology, Department of Medicine, CWRU, Cleveland OH 2000 Associate Professor with tenure, Case Western Reserve University 2001-2005 Associate Staff Scientist and Co-Director of the Program in Transplantation Research, Depts. Of Immunology and the Glickman Urologic Institute, Cleveland Clinic Foundation, Cleveland OH 2005-2006 Staff Scientist and Co-Director of the Program in Transplantation Research, Depts. Of Immunology, Nephrology and the Glickman Urologic Institute, Cleveland Clinic Foundation, Cleveland OH 2006-present Professor of Medicine, Division of Nephrology, Recanati Transplant Institute, Director of Transplant Research, The Mount Sinai School of Medicine, NY, NY Awards and Other Professional Activities 1992-1997 Clinical Investigator Award, NIH #1 KO8 DK02125-01. 1997-1998 Clerkship Teaching Award, Dept. of Medicine, Case Western Reserve University

1999-2002 National Kidney Foundation Clinical Scientist Award, May 2000 American Society of Transplantation Young Investigator’s Award, March 2009 Elected to American Association of Physicians Sept 2010 Irene and Arthur Fishberg Chair in Medicine May 2011 Established Investigator Award, American Society of Transplantation C. Peer-Reviewed Articles (selected from > 130 publications) Review Articles: Cravedi P, van der Touw W, Heeger PS. Complement regulation of T-cell alloimmunity. Semin Nephrol 2013;33:565-574. PMCID: 3884575 Relevant Original Publications: 1. Heeger PS, Greenspan NS, Kuhlenschmidt S, Dejelo C, Hricik DE, Schulak JA, and Tary-Lehmann M. Pretransplant frequency of donor-specific, interferon gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of post transplant kidney rejection episodes J Immunol, 163:2267-2275,1999 PMID: 10438971 2. Valujskikh A, Lantz O, Celli S, Matzinger P and Heeger PS. Cross-primed CD8 T cells mediate graft rejection via a distinct effector pathway. Nature Immunology 3: 844-51, 2002. PMID: 12172545 3. PS. Heeger, Feng Lin, Peter N. Lalli, Anna Valujskikh, Jinbo Liu, Yuanyuan Ma, and M. Edward Medof. Decay Accelerating Factor modulates induction of T cell immunity. J Exp Med, 201: 1523-1530, 2005 PMCID: PMC2212927 4. Peter N. Lalli, Michael G. Strainic, Feng Lin, M. Edward Medof, and Peter S. Heeger. C5a functions through T cell expressed C5aR to enhance T cell expansion by limiting T cell apoptosis Blood 112: 1759-66, 2008 accompanied by an editorial. PMCID: 2518884

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5. Vasile Pavlov, Hugo Raedler, Shuguang Yuan, Staci Leisman, Wing-hong Kwan, Peter N. Lalli, M. Edward Medof and Peter S. Heeger. Donor deficiency of decay accelerating factor accelerates murine T cell mediated cardiac allograft rejection J Immunol 181: 4580-4589, 2008 PMCID: PMC2646462 6. Hugo Raedler, Min Yang, Peter N. Lalli, M. Edward Medof, Peter S. Heeger. T cell responses to allogeneic endothelial cells are controlled by local complement activation. Amer. J. Transplantation 9:1784-95, 2009 PMID: 19563342 7. Marvin Lin, Barbara Murphy, M. Edward Medof, Peter S. Heeger*, Bernd Schröppel*. *co senior authors. Immune cell derived C3 is required for autoimmune diabetes induced by multiple low doses of streptozotocin Diabetes 59:2247-52, 2010. PMCID: 2927947 8. Daigo Hashimoto, Andrew Chow, Melanie Greter, Yvonne Saenger, Wing-Hong Kwan, Marylene Leboeuf, Florent Ginhoux, Jordi C. Ochando, Yuya Kunisaki, Nico van Rooijen, Chen Liu, Takanori Teshima, Peter S. Heeger, E. Richard Stanley, Paul S. Frenette, Miriam Merad. Pre-transplant CSF1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. Journal of Experimental Medicine 208:1069-82, 2011. PCMID 3092347 9. H Raedler*, M Vieyra*, S Leisman, P Lakhani, W Kwan, M Yang, K. Johnson, S.J. Faas, P Tamburini, PS Heeger. Anticomplement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice, *co first authors, Am J Transplantation, 11: 1397–1406 2011 PCMID 3128644 10. Deirdre Sawinski, Jaime Uribarri, Denise Peace, Tina Yao, Praeophayom Wauhop, Paulina Trzcinka, Katya Ostrow, Emilio D. Poggio and Peter S. Heeger, 25-OH Vitamin D

11.

12.

13.

14.

deficiency and cellular alloimmunity as measured by panel of reactive T cell testing in dialysis patients. Am J Transplantation 10: 2287-95, 2010. PMCID: PMC2948589 Kalache, S., R. Dinavahi, S Pinney, A Mehrotra, MW Cunningham and PS Heeger. (2011). "Anticardiac myosin immunity and chronic allograft vasculopathy in heart transplant recipients." J Immunol 187(2): 1023-1030. PMCID 3131454 Wing-hong Kwan, William van der Touw, Estela Paz-Artal, Ming O. Li, Peter S. Heeger. Signaling through C5a Receptor and C3a Receptor Modulates Function of Natural Regulatory T cells in Mice J Experimental Medicine 210: 25768, 2013 PMCID 3570105 William van der Touw, Paolo Cravedi, Wing-hong Kwan, Estela Paz-Artal, Miriam Merad, Peter S. Heeger. Cutting Edge: Receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. Journal of Immunology 190:5921 2013 PMCID: 3679341. Cravedi P, Leventhal J, Lakhani P, Ward SC, Donovan MJ, Heeger PS. Immune cell-derived c3a and c5a costimulate human T cell alloimmunity. Am J Transplant 2013;13:25302539. PMCID: 3809075

 

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BIOGRAPHICAL SKETCH NAME Li, Xiu-Min EDUCATION/TRAINING INSTITUTION AND LOCATION Henan School of Chinese Med. Zhengzhou, China China Academy of Chinese Med. Beijing, China Johns Hopkins University, Baltimore, MD A. Personal Statement As a Professor of Pediatrics and Immunobiology at Pediatric Allergy and Immunology at Icahn School of Medicine at Mount Sinai, I have combined expertise in allergy, molecular biology and medicinal natural products. I am director of Center for Integrative Medicine for Allergies and Wellness. Investigation of safe and effective natural products/compounds and immunotherapy for treating and preventing allergy and asthma is my main research area. My research funds come from NIH, industry, private organization and individual gifts. Over the past 15 years, I have received approximately $14 million in funds for my research. Through a center grant funded by NIH/NCCAM, in which I served as PI, we established a well-equipped botanical chemistry laboratory with instrument and personnel resources needed to characterize anti-allergic/inflammatory compounds in herbal products and to ensure quality and consistency of products used in laboratory and clinical studies. Two natural products developed in my laboratory are classified as US FDA Investigational New Drugs for phase II studies for food allergy and asthma respectively. Through these projects, I established national and international collaborations. I am also faculty of Mount Sinai Graduate School and mentor of masters and PhD students, clinical and research fellows. B. Positions and Honors 166

POSITION TITLE Professor of Pediatrics DEGREE MD MS Post-Doc

MM/YY 09/78-07/83 09/84-07/87 04/94-07/96

FIELD OF STUDY Medicine Medicine Allergy & Immunology

Positions and Employment 1983 – 84 Medical Resident, Luoyang Geology Ministry Staff Hospital, China. 1987 – 89 Medical Resident Department of Pediatrics, China-Japan Friendship Hospital, China 1989 – 93 Attending Physician, Department of Pediatrics, China-Japan Friendship Hospital, China 1993 – 94 Visiting Scientist, Allergy and Immunology Division, Department of Pediatrics. Stanford Medical Center, Stanford University. Palo Alto, CA 1994 – 96 Postdoctoral Fellow, Clinical Immunology Division, School of Medicine, The Johns Hopkins University, Baltimore, MD 1996 – 97 Instructor in Medicine, Clinical Immunology Division, School of Medicine, The Johns Hopkins University, Baltimore, MD 1997 – 98 Research Assistant Professor, Allergy and Immunology Division, Department of Pediatrics, The Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY 1998 – 04 Assistant Professor, Allergy and Immunology Division, Department of Pediatrics, The Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY 1999 – 04 Assistant Professor of Immunobiology (2nd appointment), Clinical Immunology and Molecular Biology

Division, The Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY 2004 – 06 Associate Professor, Allergy and Immunology Division, Department of Pediatrics, The Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY 2006 – 09 Associate Professor with tenure, Allergy and Immunology Division, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 2009 – Professor with tenure, Allergy and Immunology Division, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York Other Experience and Professional Memberships 1990 – 94 Member of Academy of Integrated Traditional Chinese and Western Medicine 1994 – 96 Member of the Johns Hopkins Medical Institutions Postdoctoral Fellow Association 1994 – Member of American Academy of Allergy Asthma and Immunology 2000 – Member of American Association of Oriental Medicine 2001 – Member of American Association of Immunologists Honors (selected) 1995 Allen & Hanbury’s Respiratory Disease Research Award, American Academy of Allergy, Asthma, and Clinical Immunology. 2003 – 2010 Member, Committee of Complementary & Alternative Medicine Practices in Allergy, American Academy of Allergy Asthma and Immunology 2003 – Organizing committee Chair, Building Bridge for Traditional Chinese Medicine 2009Gail G Shapiro Memorial Lectureship. American Academy of Allergy, Asthma and Immunology.

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2010 – 2011 Vice Chairman, Complementary & Alternative Practices in Allergy, American Academy of Allergy Asthma and Immunology 2010 – Chairman, the First East-West Scientific Conference on Allergy & Traditional Medicine (EWAT) 2011 – Chairman, Committee of Complementary & Alternative Practices in Allergy, American Academy of Allergy Asthma and Immunology 2011 – Editor, Evidence-Based Complementary and Alternative Medicine 2013- Editor, Journal of Integrative Medicine C. Selected publications (selected from 85 publications starting 2005) 1. Srivastava KD, Kattan JD, Zou ZM, Li JH, Zhang L, Wallenstein S, Goldfarb J, Sampson HA and Li X-M. The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol 2005; 115(1):171-8. 2. Wen MC, Wei CH, Hu ZQ, Srivastava K, Ko J, Xi ST, Mu DZ, Du JB, Li GH, Wallenstein S, Sampson HA, Kattan M, Li X-M. Efficacy and tolerability of anti-asthma herbal medicine intervention in adult patients with moderate-severe allergic asthma. J Allergy Clin Immunol 2005; 116(3):517-24. 3. Busse PJ, Zhang TF, Srivastava K, Lin BP, Schofield B, Sealfon SC, Li X-M. Chronic exposure to TNF-alpha increases airway mucus gene expression in vivo. J Allergy Clin Immunol 2005; 116(6):1256-63. 4. Berin MC, Zheng Y, Domaradzki M, Li X-M, Sampson HA. Role of TLR4 in allergic sensitization to food proteins in mice. Allergy 2006; 61(1):64-71. 5. Ko J, Lee JI, Munoz-Furlong A, Li X-M, Sicherer SH. Use of complementary and alternative medicine by food-allergic patients. Ann Allergy Asthma Immunol 2006; 97(3):365-9.

6. Qu C, Srivastava K, Ko J, Zhang TF, Sampson HA, Li X-M. Induction of tolerance after establishment of peanut allergy by the food allergy herbal formula-2 is associated with upregulation of interferon-gamma. Clin Exp Allergy 2007; 37(6):846-55. 7. Busse PJ, Zhang TF, Srivastava K, Schofield B, Li X-M. Effect of ageing on pulmonary inflammation, airway hyperresponsiveness and T and B cell responses in antigensensitized and -challenged mice. Clin Exp Allergy 2007; 37(9):1392-403. 8. Kattan J, Srivastava KD, Zou Z, Goldfarb J, Sampson HA, Li X-M. Pharmacologic and immunologic effects of individual herbs in the food allergy herbal formula-2 (FAHF-2) on peanut allergy. Phytotherapy Research. 2008; 22(5):651-9. 9. Zhang,T., Pan, W., Takebe, M. Schofield, B. Sampson, H. Li, X-M. Therapeutic effects of a fermented soy product on peanut hypersensitivity is associated with modulation of Th1 and Th2 responses. Clin Exp. Allergy. 2008; 38:1808-1818. 10. Jayaprakasam B, doddaga S, Wang R, Holmes D, Goldfarb J, Li, X-M. Licorice FlavonoidsInhibit Eotaxin-1 Secretion by Human Fetal Lung Fibroblasts in vitro. J Agric Food Chem. 2009;57:820-825. 11. Li X, Chauhn A , Shiekh AM., Patil S , Chauhn V , Li X-M , Ji L, Brown T, and Malik M. Elevated Immune Response in the Brain of Autistic Patients. J Neuroimmunol. 2009; 207:111-116. 12. Srivastava K, Qu C, Zhang TF, Goldfarb J, Sampson HA, Li XM. FAHF-2 silences peanut-induced anaphylaxis for a prolonged post-treatment period via IFN-γ producing CD8+T cells. J Allergy Clin Immunol. 2009;123:443-51. 13. Li X-M, Wang QF, Schofield B, Lin J, Huang SK, Wang Q. Modulation of antigen-induced anaphylaxis in mice by a traditional Chinese medicine formula, guo min kang. Am J Chin Med. 2009; 37:113-25.

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14. Kelly-Pieper K, Patil SP, Busse P, Yang N, Sampson H, Wisnivesky J, Li X-M, Kattan M.: Safety and tolerability of an antiasthma herbal formula (ASHMITM) in adult asthmatics: a randomized, double-blinded, placebo-controlled, dose escalation phase I study. J Altern Complement Med. Volume 2009; 15:735–743. 15. Paula JB, Zhang TF, Schofield B, Kilaru K, Patil S, Bezdecny S and Li X-M. Treatment with anti-tumor necrosis factor alpha decreases airway mucus gene expression in a murine model of allergic asthma. Ann Allergy Asthma Immunol. 2009 Oct;103(4):295-303. 16. López-Expósito I,Song Y, Järvinen K M, Srivastava K and Li XM. Maternal peanut exposure during pregnancy and lactation reduces peanut allergy risk in offspring. J Allergy Clin Immunol. 2009 Nov;124(5):1039-46. 17. Zeng J, Yang N, Li X-M, Shami PJ and Zhang J. 4'-OMethylglycosylation of Curcumin by Beauveriabassiana. Natural Product Communications 2009. (4): 1-4. 18. Zhang T, Srivastava K, Wen M-C, Yang N, Cao J, Busse P, Birmingham N, Goldfarb J, and Li, X-M. Pharmacology and immunological actions of an herbal medicine, ASHMITM for allergic asthma. Phytother Res. 2010. 24(7):1047-55. 19. Roy A, Lurslurchachai L, Halm EA, Li X-M, H Leventhal, Wisnivesky JP. Use of herbal remedies and adherence to inhaled corticosteroids among inner-city asthmatic patients. Ann Allergy Asthma Immunol. 2010. 104(2):132-8. 20. Paula JB, Zhang TF, Yang N, Wen M-C, Srivastava K, Schofield B, Li X-M. The traditional Chinese herbal formula ASHMI ™ inhibits allergic lung inflammation in antigen sensitized and challenged aged mice. Ann Allergy Asthma Immunol. 2010;104(3):236-46. 21. Srivastava K, Zhang T, Yang N, Sampson H, and Li X-M. Anti-Asthma Simplified Herbal Medicine Intervention-

induced long-lasting tolerance to allergen exposure in an asthma model is interferon-γ, but not transforming growth factor-β dependent. Clin Exp Allergy. 2010 Nov;40(11):167888 22. Wang J, Patil S, Yang N, Ko J, Lee J, Noone S, Sampson H and Li X-M. Safety, tolerability, and immunologic effects of a food allergy herbal formula (FAHF-2) in food allergic individuals: a randomized, double-blinded, placebocontrolled, dose escalation phase I study. Ann Allergy Asthma Immunol. 2010;105(1):75-84. 23. Song Y, Qu C, Srivastava K, Yang N, Busse P, Zhao W, Li X-M. Food Allergy Herbal Formula -2 protection against peanut anaphylactic reaction is via inhibition of mast cells and basophils. J Allergy Clin Immunol. 2010;126:1208-17. 24. Srivastava K, Chen Y, Yan N, Lopez-Exposito I, Song Y, Goldfarb J, Zhang J, Sampson H, Li X-M. Efficacy, safety and immunological actions of butanol-extracted FAHF-2 on peanut anaphylaxis. Clin Exp Allergy. 2011;41:582-91. 25. SP Patil, Wisnivesky JP, Busse PJ, Halm EA, and X-M Li. Detection of immunological biomarkers correlated with asthma control and quality of life measurements in sera from chronic asthmatic patients. Ann Allergy Asthma Immunol. 2011;106(3):205-13. 26. Wei Y, Epstein SP, Fukuoka S, Birmingham NP, Li X-M, Asbell PA. sPLA2-IIa Amplifies Ocular surface Inflammation in the Experimental Dry Eye (DE) BALB/c Mouse Model. Invest Ophthalmol Vis Sci. 2011. Jul 1;52(7):4780-8. 27. López-Expósito I, Järvinen KM., Alexandra C, Seppo AE, Song Y, and Li X-M. Maternal peanut consumption provides protection in offspring against peanut sensitization that is further enhanced when co-administered with bacterial mucosal adjuvant. Food Research International 2011. Food Res Int. 2011 Jul;44(6):1649-1656.

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28. Patil P, Wang J, Song Y, Noone S, Yang N, Wallenstein S, Sampson HA, and Li X-M. Clinical safety of FAHF-2, and inhibitory effect on basophils from patients with food allergy – extended phase I study. J Allergy Clin Immunol. 2011 Dec;128(6):1259-1265. 29. López-Expósito I, Castillo A, Yang N, Liang B and Li XM.Chinese herbal extracts of Rubia cordifolia and Dianthus superbus suppress IgE production and prevent peanutinduced anaphylaxis. Chin Med. 2011 Sep 30;6:35. 30. Srivastava K, Bardina L, Sampson H, X-M Li. Efficacy and immunological actions of FAHF-2 in a murine model of multiple food allergies. Ann Allergy Asthma Immunol. 2012 May;108(5):351-358.e1. 31. Yang N, Patil S, Zhu-ge J,Wen M-C, Bolleddula J, Doddaga S, Goldfarb J, Sampson H, and Li X-M. Licorice flavonoids present in anti-asthma formula, ASHMITM, inhibit memory Th2 responses in vitro and in vivo. Phytother Res. 2013 Sep;27(9):1381-91. 32. Reid-Adam J, Yang N, Song Y, Cravedi P, Li X-M*, P Heeger*Immunosuppressive Effects of Traditional Chinese Herb Qu Mai on Human Alloreactive T Cells. Am J Transplant. 2013 Feb 22. doi: 10.1111/ajt.12180. [Epub ahead of print] (* equal senior author). 33. Birmingham JM., Patil S, Li X-M, Busse PJ. The effect of oral tolerance on the allergic airway response in young and aged mice. Journal of Asthma. J Asthma. 2013 Mar;50(2):122-32. 34. Jayaprakasam B, Yang N, Wen MC, Wang R, Goldfarb J, Sampson H, Li XM. Constituents of the anti-asthma herbal formula ASHMI(TM) synergistically inhibit IL-4 and IL-5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro. J Integr Med. 2013 Mar;11(3):195-205.

35. Yang N, Liang B, Srivastava K, Zeng J, Zhan J, Brown L, Sampson H, Goldfarb J, Emala C, Li XM. The Sophora flavescens flavonoid compound trifolirhizin inhibits acetylcholine induced airway smooth muscle contraction. Phytochemistry. 2013 Nov;95:259-67. 36. Srivastava K, Sampson H, Emala C, Li X-M. The anti-asthma herbal medicine ASHMI acutely inhibits airway smooth muscle contraction via prostaglandin E2 activation of EP2/EP4 receptors. Am J Physiol Lung Cell Mol Physiol. 2013 Dec;305(12):L1002-10. PMCID: 37. PMC3882537 38. Song Y, Dunkin D, Dahan S, Luga A, Ceballos C, HoffstadterThal K, Yang N, Benkov K, Mayey L, and Li X-M. Antiinflammatory Effects of the Chinese Herbal Formula FAHF2 in Experimental and Human IBD. Inflamm Bowel Dis. 2014 Jan;20(1):144-53.

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BIOGRAPHICAL SKETCH NAME Lira, Sergio A. EDUCATION/TRAINING INSTITUTION AND LOCATION Universidade Federal de Pernambuco, Recife, Brazil Universidade Federal de Pernambuco, Recife, Brazil University of California, San Diego Roche Institute for Molecular Biology. Nutley, NJ A. Personal Statement. I am interested in several biological processes related to immune physiology and immune-mediated disease. My research throughout the years has focused on the role of chemokines and their receptors in homeostatic and pathological conditions. I have also studied the biological roles of virus-encoded chemokine receptor oncogenes and chemokine binding proteins. I have studied the role of chemokines and cytokines in lymphoid organogenesis and in autimmune conditions. My most recent studies focus on the biology of innate lymphoid cells and on the role of the microbiome and inflammation in neoplasia. B. Professional Positions: 1980 Research Assistant, Max-Planck Institut fur Biophysikalische Chemie. Gottingen, Germany 1982-1983 Assistant Professor, Physiology DepartmentUniversidade Federal de Pernambuco, Brazil 1985-1988 Research Assistant, Eukaryotic Regulatory Biology Program-University of California, San Diego 1992-1996 Head, Transgenic Unit, Division of OncologyBristol-Myers Squibb Pharmaceutical Res. Inst.

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POSITION TITLE Director, Immunology Institute DEGREE M.D. M.Sc. Ph.D. Postdoc

YEAR(s) 1982 1983

FIELD OF STUDY Medicine Physiology

1988 1988-92

Physiology & Pharmacology Cell & Developmental Biology

1996-1999 Associate Director, Department of ImmunologySchering-Plough Research Institute 1999-2000 Senior Associate Director, Department of Immunology- Schering-Plough Research Institute 2000-2002 Director, Department of Immunology- ScheringPlough Research Institute 2002-2004 Irene Diamond Associate Professor, Immunobiology- Mount Sinai School of Medicine (MSSM) 2004-2007 Professor, Immunobiology – MSSM 2007Professor, Medicine - MSSM 2007-2013 Co-Director, Immunology Institute – MSSM 2009The Leona M. and Harry B. Helmsley Charitable Trust Professor of Immunology - MSSM 2013Director, Immunology Institute – MSSM C. Awards and Other Professional Activities: 1980 Max Planck Gesellschaft (Germany) - Student Fellowship 1983-1988 Brazilian Research Council (CNPq) - PhD. Program Scholarship 1994-1996 Chairman of the Animal Care and Use Committee. Bristol Myers Squibb

1995 President's Award - Bristol-Myers Squibb Company 1998 Impact Award - Schering-Plough Research Institute 2000 Inventor’s Award - Schering-Plough Research Institute 2003 Co-organizer, Keystone Symposium on Chemokines and Chemokine Receptors. Breckenridge, Colorado, USA 2006 Chair, Gordon Research Conference on Chemotactic Cytokines, Aussois, France 2006 Elected to the Henry Kunkel Society 2008 Elected to the Association of American Physicians 2012 Co-organizer of the 2012 Keystone Symposium on Chemokines and Leukocyte trafficking 2013Appointed Member of the Board of Scientific Advisors of the National Cancer Institute (2013-2018) 2013Appointed Visiting Professor of the Southern Medical University, Guangzhou, China (Nov 2013- Nov 2016) C. Publications (out of 151 peer-reviewed publications) 1. Cook DN, Chen SC, Sullivan LM, Manfra DJ, Wiekowski MT, Prosser DM, Vassileva G, Lira SA. Generation and analysis of mice lacking the chemokine fractalkine. Mol Cell Biol, 2001:3159-65. PMCID: PMC86945 2. Holst PJ, Rosenkilde MM, Manfra D, Chen SC, Wiekowski MT, Holst B, Cifire F, Lipp M, Schwartz TW, Lira SA. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity. J Clin Invest, 2001:1789-96. PMCID: PMC209468 3. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD. Interleukin-23 rather than interleukin-12 is the critical

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cytokine for autoimmune inflammation of the brain. Nature, 2003:744-8. PMCID: in progess Grisotto MG, Garin A, Martin AP, Jensen KK, Chan P, Sealfon SC, Lira SA. The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells. J Clin Invest, 2006:1264-73. PMCID: PMC1430356 Marinkovic T, Garin A, Yokota Y, Fu Y-X, Ruddle NH, Furtado GC, Lira SA. Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J Clin Invest, 2006:2622-32. PMCID: PMC1570377 Marchesi F, Martin AP, Thirunarayanan N, Devany E, Mayer L, Grisotto MG, Furtado GC, Lira SA. CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles. Mucosal immunology, 2009:486-94. PMCID: in progress Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol, 2009:514-23. PMCID: in progress Shang L, Thirunarayanan N, Viejo-Borbolla A, Martin A, Bogunovic M, Marchesi F, Unkeless J, Ho Y, Furtado GC, Alcami A, Merad M, Mayer L, Lira S. Expression of the chemokine binding protein M3 promotes marked changes in the accumulation of specific leukocytes subsets within the intestine. Gastroenterology, 2009:1006-18. PMCID: PMC2736321 Méndez-Ferrer S., Michurina TV, Ferraro F, Mazloom AR, MacArthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS. Mesenchymal and haematopoietic stem

   

10.

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14. 15.

cells form a unique bone marrow niche. Nature, 2010:82934. PMCID: PMC3146551 Viejo-Borbolla A, Martin AP, Muniz LR, Shang L, Marchesi F, Thirunarayanan N, Harpaz N, Garcia RA, Apostolaki M, Furtado GC, Mayer L, Kollias G, Alcami A, Lira SA. Attenuation of TNF-driven murine ileitis by intestinal expression of the viral immunomodulator CrmD. Mucosal Immunol. 2010:633-644. PMCID: PMC2979317 Bongers G, Maussang D, Muniz LR, Noriega VM, FraileRamos A, Barker N, Marchesi F, Thirunarayanan N, Vischer HF, Qin L, Mayer L, Harpaz N, Leurs R, Furtado GC, Clevers H, Tortorella D, Smit MJ and Lira SA. The cytomegalovirusencoded chemokine receptor US28 promotes intestinal neoplasia in mice. J Clin Invest, 2010:3969-3978. PMCID: PMC2964974 Ouyang X, Zhang R, Yang J, Li Q, Qin L, Zhu C, Liu J, Ning H, Shin MS, Gupta M, Qi CF, He JC, Lira SA, Morse HC 3rd, Ozato K, Mayer L, Xiong H. Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation. Nat Commun, 2011:314. PMCID:PMC3112536 Medina-Contreras O, Geem D, Laur O, Williams IR, Lira SA, Nusrat A, Parkos CA, Denning TL. CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J Clin Invest, 2011:4787-95. PMCID:PMC3226003 Lira SA, Furtado GC. The biology of chemokines and their receptors. Immunol Res., 2012:111-20. PMCID: in progess Bongers G, Muniz LR, Pacer ME, Iuga AC, Thirunarayanan N, Slinger E, Smit MJ, Reddy EP, Mayer L, Furtado GC, Harpaz N, Lira SA. A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans. Gastroenterology, 2012:730-40. PMCID:PMC3431560

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16. Islam SA, Chang DS, Colvin RA, Byrne MH, McCully ML, Moser B, Lira SA, Charo IF, Luster AD. Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells. Nat Immunol 2011;12:167-177. PMCID: PMC2964974 17. Nagao K, Kobayashi T, Moro K, Ohyama M, Adachi T, Kitashima DY, Ueha S, Horiuchi K, Tanizaki H, Kabashima K, Kubo A, Cho YH, Clausen BE, Matsushima K, Suematsu M, Furtado GC, Lira SA, Farber JM, Udey MC, Amagai M. Stressinduced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat Immunol 2012;13:744-752. PMCID: in progess 18. Farache J, Koren I, Milo I, Gurevich I, Kim KW, Zigmond E, Furtado GC, Lira SA, Shakhar G. Luminal Bacteria Recruit CD103(+) Dendritic Cells into the Intestinal Epithelium to Sample Bacterial Antigens for Presentation. Immunity, 2013:581-95. PMCID: in progess 19. Furtado GC1, Pacer ME, Bongers G, Bénézech C, He Z, Chen L, Berin MC, Kollias G, Caamaño JH, Lira SA. TNFα-dependent development of lymphoid tissue in the absence of RORγt+ lymphoid tissue inducer cells. Mucosal Immunol, 2013 Oct 16. PMID: 2412916. 20. Berres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, Idoyaga J, Ruzo A, Lupo PJ, Hicks MJ, Shih A, Simko SJ, Abhyankar H, Chakraborty R, Leboeuf M, Beltrão M, Lira SA, Heym KM, Bigley V, Collin M, Manz MG, McClain K, Merad M, Allen CE. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014 Apr 7;211(4):669-683. Epub 2014 Mar 17. PMID: 24638167 21. Bongers G, Pacer ME, Geraldino TH, Chen L, He Z, Hashimoto D, Furtado GC, Ochando J, Kelley KA, Clemente JC, Merad M, van Bakel H, Lira SA. Interplay of host

microbiota, genetic perturbations, and inflammation promotes local development of intestinal neoplasms in mice. J Exp Med. 2014 Mar 10;211(3):457-72. doi: 10.1084/jem.20131587. Epub 2014 Mar 3. PMID:24590763; PMCID: PMC3949565.

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BIOGRAPHICAL SKETCH NAME Masilamani, Madhan EDUCATION/TRAINING INSTITUTION AND LOCATION University of Madras, Chennai, India Pondicherry University, Pondicherry, India University of Konstanz, Konstanz, Germany National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD Positions and Employment 1999-2003 Scientific Assistant/Graduate Student, Department of Biology, University of Konstanz, Germany 2003-2008 Postdoctoral Visiting Fellow, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD Dec 2007 Assistant Professor, Division of Allergy and Immunology, Department of Pediatrics, Mount Sinai School of Medicine, New York, NY Other Experience and Professional Memberships 2004- Member, American Association of Immunology 2008- Member, American Association of Allergy, Asthma and Immunology 2008- Ad-hoc Reviewer: The Journal of Immunology, The Journal of Allergy and Clinical Immunology, PLoS-ONE, Food and Chemical Toxicology, European Journal of Clinical Nutrition Honors 1994 National Merit Scholarship, Ministry of Human Resource and Development, Government of India 1994 Junior Fellowship, Indian Council of Agricultural Research (ICAR), Ministry of Agriculture, Government of India 175

POSITION TITLE Assistant Professor DEGREE B.Sc. M.Sc. Ph.D.

MM/YY 1994 1997 2003

FIELD OF STUDY Biochemistry Medical Biochemistry Natural Sciences

Postdoctoral

2007

Immunology

1997 Junior Research Fellowship, Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India 2003 Postdoctoral Visiting Fellowship, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 2006 Fellows Award for Research Excellence, National Institutes of Health, Bethesda, MD 2008 Fellows Award for Research Excellence, National Institutes of Health, Bethesda, MD 2009 American Association of Immunology- Junior Faculty Travel Grant Selected Peer-reviewed Publications (Publications selected from 29 peer-reviewed publications) 1. Masilamani M, Apell HJ, Illges H. Purification and characterization of soluble CD21 from human plasma by affinity chromatography and density gradient centrifugation. J Immunol Methods. 2002 Dec 1;270(1):11-8. 2. Rajendran L, Masilamani M, Solomon S, Tikkanen R, Stuermer CA, Plattner H, Illges H. Asymmetric localization of Flotillins/Reggies in pre-assembled platforms confers inherent polarity to haematopoietic cells. Proc Natl Acad Sci

U S A. 2003 Jul 8;100(14):8241-6. 3. Masilamani M, Kassahn D, Mikkat S, Glocker MO, Illges H. B cell activation leads to shedding of complement receptor type II (CR2/CD21). Eur J Immunol. 2003 Sep;33(9):2391-7. 4. Masilamani M, von Kempis J, Illges H. Decreased levels of serum soluble complement receptor-II (CR2/CD21) in patients with rheumatoid arthritis. Rheumatology (Oxford). 2004 Feb;43(2):186-90. 5. Sanni TB, Masilamani M, Kabat J, Coligan JE, Borrego F. Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse. Mol Biol Cell. 2004 Jul;15(7):3210-23. PMCID: PMC452577 6. Masilamani M, Nowack R, Witte T, Schlesier M, Warnatz K, Glocker MO, Peter HH, Illges H. Reduction of soluble complement receptor 2/CD21 in systemic lupus erythomatosus and Sjogren's syndrome but not juvenile arthritis. Scand J Immunol. 2004 Dec;60(6):625-30. 7. Fattakhova G, Masilamani M, Borrego F, Gilfillan AM, Metcalfe DD, Coligan JE. The high affinity IgE receptor (FceRI) is endocytosed by an AP-2/clathrin-independent mechanism. Traffic. 2006 Jun;7(6):673-85. 8. Masilamani M, Nguyen C, Kabat J, Borrego F, Coligan JE. CD94/NKG2A inhibits natural killer cell activation by disrupting the actin network at the immunological synapse. J Immunol. 2006 Sep 15;177(6):3590-6. 9. Masilamani M, Narayanan S, Prieto M, Borrego F, Coligan JE. Uncommon Endocytic and Trafficking Pathway of the Natural Killer Cell CD94/NKG2A Inhibitory Receptor. Traffic. 2008 Jun;9(6):1019-34. 10. Fattakhova GV, Masilamani M, Narayanan S, Borrego F, Gilfillan AM, Metcalfe DD, Coligan JE. Endosomal Trafficking of the Ligated FceRI Receptor. Mol Immunol. 2009 Feb;46(5):793-802. PMCID: PMC2668543

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11. Masilamani M, Wei J, Bhatt S, Paul M, Yakir S, Sampson HA. Soybean Isoflavones regulate dendritic cell function and suppress allergic sensitization to peanut. J Allergy and Clin Immunol. 2011 Dec;128(6):1242-1250 12. Wei J, Bhatt S, Chang L, Sampson HA, Masilamani M. Isoflavones, genistein and daidzein, regulate mucosal immune response by suppressing dendritic cell function. PLoS ONE. 2012, 7(10):e47979. doi: 10.1371/journal.pone.0047979. 13. Ford LS, Bloom KA, Nowak-Węgrzyn AH, Shreffler WG, Masilamani M, Sampson HA. Basophil reactivity, wheal size, and immunoglobulin levels distinguish degree of cow's milk tolerance. J Allergy and Clin Immunol. 2013 Jan;131(1):180-186.e3. 14. Pascal M, Konstantinou GN, Masilamani M, Lieberman J, Sampson HA. In silico prediction of Ara h 2 T cell epitopes in peanut allergic children. Clin Exp Allergy. 2013. Jan;43(1):116127. 15. Caubet JC, Masilamani M, Rivers NA, Mayer L, Sampson HA. Potential non-T cells source of interleukin-4 in food allergy. Pediatr Allergy Immunol. 2014. Feb 27. doi: 10.1111/pai.12207.

BIOGRAPHICAL SKETCH NAME Mehandru, Saurabh EDUCATION/TRAINING INSTITUTION AND LOCATION University of Delhi, India University of Delhi, India New York University School of Medicine Rockefeller University Mount Sinai School of Medicine A. Personal Statement I am trained as a gastroenterologist with an interest in studying the mucosal immunity. We identified that gastrointestinal CD4+ T cells are preferentially targeted during acute HIV infection and show incomplete reconstitution with sustained and suppressive antiretroviral therapy. These findings have provided an important insight into the role of the GI tract in HIV pathogenesis and vaccine development. To study the generation of HIV specific immune cells in the GI tract, I trained with Dr. Ralph Steinman, Nobel laureate for Medicine in 2011. My laboratory focuses on studying novel pathways of migration of immune cells to the GI tract and on the induction of HIV specific immunity in the intestines. B. Positions and Honors. Positions (while in training programs, above) 2002-2003 Chief Medical Resident, New York University School of Medicine 2006-2007 Research Scientist, Aaron Diamond AIDS Research Center, New York 2009- Adjunct faculty Steinman Laboratory, Rockefeller University, New York 177

POSITION TITLE Assistant Professor in Gastroenterology DEGREE M.B.B.S (MD)

YEAR(s) 1989-1994 1995-1998 1999-2002 2003-2006 2007-2010

FIELD OF STUDY Medicine Internal Medicine Internal Medicine Postdoctoral Research in HIV biology Gastroenterology

Honors 1994 “Top graduate of the class of 1993”, Delhi University, New Delhi, India. 1997 “Best Post-graduate of the year”, Delhi University, New Delhi, India 2001 “Resident of the Year” in Internal Medicine, New York University. 2003 Housestaff Research Award, New York University, School of Medicine. 2005 Young Investigator Award. 12th Conference for Retroviruses and Opportunistic Infections, Boston, Massachusetts. 2006 Young Investigator Award. 13th Conference for Retroviruses and Opportunistic Infections, Denver, Colorado. 2007 Young Investigator Award. 14th Conference for Retroviruses and Opportunistic Infections, Los Angeles, California. 2008 Young Investigator Award. 15th Conference for Retroviruses and Opportunistic Infections, Boston, Massachusetts. 2009 Fellowship to leadership travel award, Digestive disease

week, Chicago, IL 2010 American Gastroenterology Association (AGA) Elsevier Pilot Award for research. “Eric Lemmer memorial award” for the best outgoing fellow in Gastroenterology, Mount Sinai School of Medicine C. Selected peer-reviewed publications (in chronological order). 1. Mehandru, S., Poles, M.A., Tenner-Racz, K., Horowitz, A., Hurley, A., Hogan, C., Boden, D., Racz, P. and Markowitz, M. Primary HIV-1 infection is associated with preferential depletion of CD4+ T cells from effector sites in the gastrointestinal tract. J. Exp. Med. 200:761-770, 2004. PMCID: PMC2211967 2. Bini, E.J., Mehandru, S. Incidence of interferon and ribavirininduced autoimmune hypothyroidism in a cohort of male patients with chronic hepatitis C. Archives Intl. Med.164:2371-2376, 2004. PMID: 15557418 3. Mehandru, S., Wrin, T., Galovich, J., Stiegler, G., Vcelar, B., Hurley, A., Hogan, C., Vasan, S., Katinger, H., Petropoulos, P., and Markowitz, M. Neutralization profiles of newly transmitted HIV-1 by monoclonal antibodies 2G12, 2F5 and 4E10. J. Virol.78:14039-14042, 2004. PMCID: PMC533925 4. Markowitz, M., Mohri, H., Mehandru, S., Shet, A., Berry, L., Kalyanaraman, R., Kim, A., Chung, C., Jean- Pierre, P., Horowitz, A., La Mar, M., Wrin, T., Parkin, N., Poles, M., Petropoulos, C., Mullen, M., Boden, D., and Ho, D. Infection with multidrug resistant, dual tropic HIV-1 and rapid progression to AIDS: a case report. Lancet.365:1031-1038, 2005. PMID: 15781098 11. MHC I haplotypes. Proc. Nat. Acad. Sci. USA.104:1289-1294,

2007. PMCID: PMC1783096

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5. Mehandru, S., Tenner-Racz, K., Racz, P., and Markowitz, M.

The gastrointestinal tract is critical to the pathogenesis of acute HIV-1 infection. J. Allergy Clin. Immunol.116:419-422, 2005. PMID: 16083799 6. Bini, E.J., and Mehandru, S. Sustained Virologic Response Rates and Health-Related Quality of Life after Interferon and Ribavirin Therapy in Patients with Chronic Hepatitis C Virus Infection and Persistently Normal Alanine Aminotransferase Levels. Alimentary Pharmacology and Therapeutics. 23:777-85, 2006. PMID: 16556180 7. Shet, A,, Berry, L., Mohri, H., Mehandru, S., Chung, C., Kim, A., Jean-Pierre, P., Hogan, C., Simon, V., Boden, D., and Markowitz, M. Tracking the Prevalence of Transmitted Antiretroviral Drug Resistant HIV-1: A Decade of Experience. J. Acquired Immune Deficiency Syndromes.41:439-446. 2006. PMID: 16652051 8. Mehandru, S., Poles, M.A., Tenner-Racz, K., Manuelli, V., Jean-Pierre, P., Lopez, P., Shet, A., Low, A., Mohri, H., Boden, D., Racz, P., Markowitz, M. Mechanisms of gastrointestinal CD4+ T cell depletion during acute and early HIV-1 infection. J. Virol.81:599-612, 2006. PMCID: PMC1797467 9. Mehandru, S., Poles, M.A., Tenner-Racz, K., Jean-Pierre, P., Manuelli, V., Lopez, P., Shet, A., Low, A., Mohri, H., Boden, D., Racz, P., and Markowitz, M. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. Public Library of Science, Medicine.3:e484, 2006. PMCID: PMC1762085 10. Bozzacco, L., Trumpfheller, C., Siegal, F.P., Mehandru, S., Markowitz, M., Piperno, A.G., and Steinman, R.M. The DEC 205 receptor on dendritic cells mediates presentation of HIV-1 gag protein to CD8+ T cells in a spectrum of human 12. Mehandru, S., Vcelar, B., Wrin, T., Stiegler, G., Joos, B., Mohri, H., Boden, D., Galovich, J., Tenner-Racz, K., Racz, K.,

13.

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15.

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Carrington, M., Petropoulos, P., Katinger, H., and Markowitz, M. Adjunctive passive immunotherapy in HIV-1-infected individuals treated with antiviral therapy during acute/early infection. J. Virol. 81:11016-11031, 2007. PMCID: PMC2045579 Mehandru, S., and Dandekar, S. Role of the gastrointestinal tract in establishing infection in primates and humans. Curr. Opinion in HIV and AIDS.3:22-27, 2008. PMID: 19372940 Evering TH, Mehandru S, Racz P, Tenner-Racz K, Poles MA, Figueroa A, Mohri H, Markowitz M. Absence of HIV-1 evolution in the gut associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection. Public Library of Science, Pathogens. 8: e1002506, 2012. PMID 22319447 Ruel J, Ruane DT, Mehandru S, Gower-Rousseau C and Colombel JF. Inflammatory Bowel Disease Across Ages: Is It The Same Disease? Nature Reviews Gastroenterology and Hepatology. 2013 Dec 17 (epub). PMID: 24345891 Ruane DT, Brane L, Reis B, Cheong C, Poles J, Do Y, Zhu H, Velinzon K, Choi JH, Studt N, Mayer L, Lavelle EC, Steinman RM, Mucida D and Mehandru S. Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. J Exp Med. 2013 Aug;210(9):1871-88. PMID: 23960190

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BIOGRAPHICAL SKETCH NAME Merad, Miriam

POSITION TITLE Professor

EDUCATION/TRAINING INSTITUTION AND LOCATION University of Paris VII. France Stanford University and University Paris VII. France

DEGREE M.D. Ph.D.

A. Personal Statement: Miriam Merad, M.D.; Ph.D. is a Professor of Oncological science, Medicine (Hem/Onc division) and Immunology and a Member of the Immunology Institute and The Tisch Cancer Institute at the Mount Sinai School of Medicine in New York. Dr. Merad was recruited to Mount Sinai School of Medicine in 2004 and was promoted to the rank of Associate Professor with Tenure in 2007 and to Full Professor in 2010. In 2010 Dr. Merad also became the program leader of the Cancer immunology immunotherapy group at The Tisch Cancer Institute and the director of the Human Immunomonitoring center. Dr. Merad also serves as the Associate Director for the MD PhD program at Mount Sinai Medical School. Dr. Merad’s laboratory studies the mechanisms that regulate the development and function of innate myeloid cells including dendritic cells and macrophages. In 2013, Dr. Merad was the primary organizer of the prestigious Keystone conference on dendritic cell biology and was elected to the “American Society of Clinical Investigation”. She has authored more than 100 primary papers and review articles in high profile journals and obtained extensive NIH funding for her studies on dendritic cells and macrophage biology in mice and humans. B. Positions and Honors 1991-1992 Internship in Internal Medicine.

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YEAR(s) 1992 2001

FIELD OF STUDY Medicine/ Hematology Immunology

1992-1998 Medical Residency, Internal Medicine. APHP (Hospital of Paris). France 1998-2001 PhD student in Immunology-University Paris VII/ Department of Pathology, Stanford University 2001-2003 Post doctoral Fellow, in ImmunologyDepartment of Pathology, Stanford University Assistant Professor, Department of Gene therapy and Department of Medicine, Mount Sinai School of Medicine. 2007 Associate Professor with Tenure, Department of Gene and Cell Medicine and the Department of Medicine, Mount Sinai School of Medicine. 2009 Program Leader Cancer Immunology Immunotherapy Program, Tisch Cancer Institute, Mount Sinai School of Medicine. 2010-present Professor, Department of Gene and Cell Medicine and the Department of Medicine (Hem/Onc division), Mount Sinai School of Medicine 2012 Professor, Department of Oncological Sciences, Mount Sinai School of Medicine 1999 American Association for Cancer Research 2000 American Association of Immunologists and American Association of Hematology 2005 Member of the steering committee for the “Langerhans Cell Society”

2005 Member of the Transplantation biology committee for the American Society of Hematology Ad hoc reviewer for Science, Nature, Nature Immunology, Nature Medicine, Cell, Immunity, Journal of Experimental Medicine, Journal of Clinical Investigation, Journal of Immunology, Blood, European Journal of Immunology, Hepatology, Gastroenterology. Alexandrine and Alexander L. Sinsheimer Scholar Award (20042007) Japanese Society of Immunology Scholar Award (2004) Graduate School Excellence in Teaching Award, Mount Sinai (2006) Leukemia Research Foundation Award (2006) Harold and Golden Lamport Research Award, Mount Sinai (2006) Dean’s Lecture, Mount Sinai (2007) Rosenfield Award, Mount Sinai (2008) Dean’s Award for Excellence in Translational Science (2010) Elected to the American Society of Clinical Investigation (2012) C. Selected Peer-Reviewed Publications (9 out of 115) ORIGINAL PUBLICATIONS 2014: 1. Paul Andrew Muller1, …Miriam Merad1*, Milena Bogunovic1, 3 * . 2014. Crosstalk between Muscularis Macrophages and Enteric Neurons Regulates Gastrointestinal Motility. (* equal contributors). Cell (2nd revision) 2. Arya Khosravi, Alberto Ya´ n˜ ez, Jeremy G. Price, Andrew Chow, Miriam Merad, Helen S. Goodridge, Sarkis K. Mazmanian. 2013. Gut Microbiota Promotes Hematopoiesis to Control Bacterial Infection. Cell Host & Microbes (in press) 3. Sivendran S....... Miriam Merad, Eric Schadt, Yvonne Saenger. 2014. Dissection of Immune Gene Networks in Primary Melanoma Tumors Critical for Anti-Tumor

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Surveillance of Patients with Stage II-III Resectable Disease.J. Inv. Derm. (in press) Marie-Luise Berres*1,2,3, ….Matthew Collin10, Markus G. Manz6, Kenneth McClain4,8, Miriam Merad1,2,3*, Carl E. Allen4,8*. 2014. BRAF-V600E Expression in Precursor Versus Differentiated Dendritic Cells Defines Clinically Distinct LCH Risk-Groups (* equal contributors). J. Exp. Med. (in press) Arthur Mortha1,2,3, Aleksey Chudnovskiy1,2,3, Daigo Hashimoto1,2,3**, Milena Bogunovic1,2,3*, Sean P. Spencer4, Yasmine Belkaid4 and Miriam Merad1,2,3 . 2014. Microbiotadriven crosstalk between myeloid cells and RORγt+ innate lymphoid cells controls T cell homeostasis in the gut. Science (in press) Giuliana Magri1,8, Miyajima M, Bascones S, Mortha A, Puga I, Cassis L, Barra CM, Comerma L, Chudnovskiy A, Gentile M, Llige D, Cols M, Serrano S, Aróstegui JI, Juan M, Yagüe J,Miriam Merad3,4, Sidonia Fagarasan2 & Andrea Cerutti1,4,72014. ILC integrate stromal and immune signals to enhance antibody production by splenic marginal zone B cells. Nature Immunolgy (in press). Marco Mielacrek, Yasmine Kirkorian, Robert C. Hackman, Jeremy Price, Brent L. Wood, Marylene Leboeuf, Milena Bogunovic, Rainer Storb, Yoshihiro Inamoto, Mary E. Flowers, Paul J. Martin, Matthew Collin and Miriam Merad. 2014. Langerhans cell homeostasis and turnover after nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation . Transplantation (in press) Jingjing Jiao , Ana-Cristina Dragomir , Peri Kocabayoglu , Adeeb H.Rahman, Andrew Chow, Daigo Hashimoto, Marylene Leboeuf , Thomas Kraus , Thomas Moran , Gonzalo Carrasco-Avino , Scott L. Friedman , Miriam Merad and Costica Aloman 2014. Central Role of Conventional

Dendritic Cells in Regulation of Bone Marrow Release and Survival of Neutrophils. Journal Of Immunology (in press) 9. Judith Albert Ruzo, Navpreet Tung, Alessia Baccarini, Marylene Leboeuf, Marylene Leboeuf2,3, Daigo Hashimoto2,3, Christian Becker2,3, Miriam Merad2,3, Brian D Brown1,3 2014. microRNA-126 regulates the innate response to pathogenassociated nucleic acids through multiscale control of plasmacytoid dendritic cells. Nature Immunology 15(1):5462.

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BIOGRAPHICAL SKETCH NAME Moran, Thomas M. EDUCATION/TRAINING INSTITUTION AND LOCATION Northeastern University, Boston, MA Boston University A. Personal Statement Dr. Moran has published widely on immunity to virus infection using both mouse models (ref 1, 2, 4, 6,8,9,11) and studies in or using samples from human subjects (3,5,7, 12,13,15). In addition he has led studies aimed to understand changes that occur in immune functions of women during pregnancy. He served as the Overall director of the NIH funded Center for Investigating Viral Immunity and Antagonism (CIVIA). CIVIA focused on studies of human immunology and infectious disease by advancing technological methodologies, supporting inventive research, serving as a conduit for collaboration and promoting exchange of scientific information. Among other projects, a recent study funded by CIVIA profiled the immune response of patients receiving the live-attenuated influenza virus vaccination. Dr. Moran served as overall PI for the Viral Immunity in Pregnancy study (VIP) that recently concluded. This was a study of changes that occur in women during pregnancy with an emphasis on understanding the enhanced susceptible to infection. Data from the two cohorts of the VIP studyimmune response changes during pregnancy (60 patients) and influenza vaccination during pregnancy (350 patients) were recently published. Dr. Moran is the Director of the Center for Therapeutic Antibody Development (CTAD) at The Icahn School of Medicine at Mount Sinai. The center has been active for more than 15 years and during this time produced many monoclonal 183

POSITION TITLE Professor of Microbiology and Immunology DEGREE BS PhD

MM/YY 1972 1981

FIELD OF STUDY Biological Sciences Immunology/Microbiology

antibodies against various infectious agents and other Immunogens. CTAD has a close collaboration with Medical Research Council-Technology division in London to produce and develop human or humanized monoclonal antibodies. A number of collaborative projects are in progress primarily to develop monoclonal antibodies with therapeutic applications. Technology has been developed and is currently being used by CTAD to produce human monoclonal antibodies by V gene cloning as well as fusion of human B cells expanded by various methods in vitro. B. Positions and Honors 1976-1981 Graduate Studies: Boston University Preceptor: Dr. Michael Bennett; 1981-1983 Post Doctoral Studies: University of Uppsala, Sweden Preceptor: Dr. Hans Wigzell 1983-1985 Post Doctoral Studies: Mount Sinai School of Medicine Preceptor: Dr. Constantin Bona 1986-1989 Assistant Research Professor Department of Microbiology, Mount Sinai School of Medicine 1990-1993 Associate Research Professor Department of Microbiology, Mount Sinai School of Medicine 1990-2012 Director, Center for Therapeutic Antibody Development, Mount Sinai School of Medicine 1993-2005 Associate Professor, Department of Microbiology, Mount Sinai School of Medicine

2005- Professor, Microbiology and Immunology, Mount Sinai School of Medicine 2004-2011 Director, Center for Investigation of Viral Immunity and Antagonism Peer Review: Editorial Board: Journal of Virology 2002-present Ad Hoc reviewer 1. Journal of Experimental Medicine 2. Journal of Immunology 3. Immunity 4. Blood 5. European Journal of Immunology 6. Nature Medicine 7. Plos Pathogens/Plos One 8. Infection and Immunity Professional Societies American Association for the Advancement of Science American Society of Microbiology New York Academy of Science American Association of Immunologists International Association of Medical School Educators C. Selected Peer-reviewed Publications 1. Brimnes, M., Bonifaz, L. Steinman, R. M., Moran, T.M. 2003. Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a co-administered normally nonimmunogenic protein J Exp Med 198: 133-144, 2004 PMID: 12847140 2. Bonifaz, L. C., D. P. Bonnyay, A. Charalambous, D. I. Darguste, S. Fujii, H. Soares, M. K. Brimnes, B. Moltedo, T. M. Moran, and R. M. Steinman. 2004. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med 199:815-24. PMID: 15024047

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3. Escribese, M. M., T. Kraus, E. Rhee, A. Fernandez-Sesma, C. B. Lopez, and T. M. Moran. 2008. Estrogen inhibits dendritic cell maturation to RNA viruses. Blood 112:4574-4584 PMID: 18802009 4. Moltedo, B., C. B. Lopez, M. Pazos, M. I. Becker, T. Hermesh, and T. M. Moran. 2009. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity. J Immunol 183:3569-3573. PMID: 19717515 5. Phipps-Yonas, H., J. Seto, S. C. Sealfon, T. M. Moran, and A. Fernandez-Sesma. 2008. Interferon-beta pretreatment of conventional and plasmacytoid human dendritic cells enhances their activation by influenza virus. PLoS Pathog 4:e1000193. 6. Moltedo, B., W. Li, J. S. Yount, and T. M. Moran. 2011. Unique type I interferon responses determine the functional fate of migratory lung dendritic cells during influenza virus infection. PLoS Pathog 7:e1002345. PMID: 22072965 7. Fernandez-Sesma, A., S. Marukian, B.J. Ebersole, D. Kaminski, M.S. Park, T. Yuen, S.C. Sealfon, A. Garcia-Sastre, and T.M. Moran. 2006. Influenza Virus Evades Innate and Adaptive Immunity via the NS1 Protein. J Virol 80:62956304. PMID: 16775317 8. Pica, N., R. Hai, F. Krammer, T. T. Wang, J. Maamary, D. Eggink, G. S. Tan, J. C. Krause, T. Moran, C. R. Stein, D. Banach, J. Wrammert, R. B. Belshe, A. Garcia-Sastre, and P. Palese. 2012. Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses. Proc Natl Acad Sci U S A 109:2573-8 9. Wang, T.T., G.S. Tan, R. Hai, N. Pica, L. Ngai, D.C. Ekiert, I.A. Wilson, A. Garcia-Sastre, T.M. Moran, and P. Palese. 2010. Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct

viral subtypes. Proc Natl Acad Sci U S A 107:18979-18984. PMID: 209562931. PMCID: PMC2973924 10. Hermesh, T., B. Moltedo, T. M. Moran, and C. B. Lopez. 2010. Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell Host Microbe 7:343-353. PMID: 20478536 PMCID: PMC287420 11. Sperling, R. S., S. M. Engel, S. Wallenstein, T. A. Kraus, J. Garrido, T. Singh, L. Kellerman, and T. M. Moran. 2012. Immunogenicity of trivalent inactivated influenza vaccination received during pregnancy or postpartum. Obstet Gynecol 119:631-9. 12. Kraus, T. A., S. M. Engel, R. S. Sperling, L. Kellerman, Y. Lo, S. Wallenstein, M. M. Escribese, J. L. Garrido, T. Singh, M. Loubeau, and T. M. Moran. 2012. Characterizing the pregnancy immune phenotype: results of the viral immunity

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and pregnancy (VIP) study. J Clin Immunol 32:300-11. PMID: 22198680 13. Li, W., B. Moltedo, and T. M. Moran. 2012. Type I Interferon Induction during Influenza Virus Infection Increases Susceptibility to Secondary Streptococcus pneumoniae Infection by Negative Regulation of gammadelta T Cells. J Virol 86:12304-12. PMID: 22951826 14. Barria, M. I., J. L. Garrido, C. Stein, E. Scher, Y. Ge, S. M. Engel, T. A. Kraus, D. Banach, and T. M. Moran. 2013. Localized mucosal response to intranasal live attenuated influenza vaccine in adults. J Infect Dis 207:115-24. PMID: 23087433 15. Geyer AI, Kraus T, Roberts M, Wisnivesky J, Eber CD, Hiensch R, Moran TM. 2013 Plasma level of interferon γ induced protein 10 is a marker of sarcoidosis disease activity. Cytokine. Oct;64(1):152-7. Epub 2013 Jul 27. PMID:23899720

BIOGRAPHICAL SKETCH NAME Murphy, Barbara T. EDUCATION/TRAINING INSTITUTION AND LOCATION The Royal College of Surgeons The Royal College of Physicians The Royal College of Physicians A. Personal Statement The focus of my research has been in transplant immunology and transplant genomics for which I have had NIH funding for 19 years. My research focuses on the role of genetics and genomics in the prediction of clinical and pathological outcomes in transplantation. I am the PI of a large multicenter grant entitled “Genomics of Chronic Allograft Rejection” (GoCAR). GoCAR is one of the largest prospective studies in transplantation brining together investigators in seven institutions and two continents. B. Positions and Honors Internship and Residency: July1989- June 1990: Internship, Beaumont Hospital, Dublin, Ireland. July 1990 - June1992: Residency Rotation, Beaumont Hospital, Dublin. July 1992-June 1993: Clinical Nephrology, Fellow, Beaumont Hospital, Dublin. July 1993 -May 1997: Nephrology Fellow, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston Hospital Appointments: 1997 - 2005 Director of Transplant Nephrology, Mount Sinai Hospital, New York 186

POSITION TITLE Professor DEGREE MB BAO MRCPI FRCPI

MM/YY 1989 1992 1998

FIELD OF STUDY Medicine Medicine Medicine

2003 - 2004 Interim Chief of Nephrology, Mount Sinai School of Medicine, New York 2004 - 2013 Chief, Division of Nephrology, Mount Sinai School of Medicine, New York 2012 - Chair, Department of Medicine, Mount Sinai School of Medicine, New York Academic Appointments: 1997 – 2003 Assistant Professor of Medicine, Mount Sinai School of Medicine, New York 2003- 2007 Associate Professor of Medicine, Mount Sinai School of Medicine, New York 2008 Professor of Medicine, Mount Sinai School of Medicine, New York 2011 - 2012 Dean for Clinical and Population based Research 2011 - 2012 Director of Conduits, The Institute for Translational Science 2012 - Chair Department of Medicine, Icahn School of Medicine at Mount Sinai 2013 - Dean for Clinical Integration and Population Based Health Honors and Awards 1994 Young Investigator Award, American Society of Transplant Physicians. 1996 Young Investigator Award, American Society of

Transplant Physicians. 1994- 1996 ASTP/Sandoz Fellowship Award, American Society of Transplant Physicians. 2003 Young Investigator Award, Basic Science. American Society of Transplantation 2003 – 2005 Chair, Transplant Advisory Group, American Society of Nephrology 2003 – 2004 Chair, Education Committee American Society of Transplantation 2004 - Member AITRC Study Section, NIAID/NIH 2004 Irene and Dr. Arthur M. Fishberg Professor of Medicine 2004 - 2007 American Society of Transplantation, Councilorat-Large 2005 - 2007 Executive Committee, ATC Program Committee, and Chair 2007 ATC 2007 President Elect, American Society of Transplantation 2008 President, American Society of Transplantation 2009 Past-President, American Society of Transplantation 2011 American Kidney Fund Nephrologist of the Year 2013 - Chair, Program Committee, World Transplant Congress 2014 2013 Murray M. Rosenberg Professor of Medicine C. Selected from over 70 peer-reviewed publications (in chronological order). 1. Murphy B, Magee CC, Alexander SI, Snoeck HW, Vella JP, Carpenter CB and Sayegh MH. Inhibition of allorecognition by a human class II MHC derived peptide through the induction of apoptosis. JCI 1999; 103: 859-867. PMID:10079107 2. Marder B, Schröppel B, Lin M, Schiano T, Tomer Y, Murphy B. Influence of Costimulatory Molecule Gene Polymorphisms

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on Clinical Outcomes in Liver Tranplantation. Am J Transplant 2003; 3: 424-31. PMID:12694064 Murphy B, Yu J, Jiao Q, Lin M, and Sayegh M.H. A novel mechanism for the immunomodulatory functions of class II MHC derived peptides. JASN 2003; 14:1053-1065. PMID:12660341 Schroppel B, Zhang N, Chen P, Zang W, Chen D, Hudkins KL, Kuziel W, Sung R, Bromberg JS, Murphy B. Differential expression of Chemokines and Chemokine Receptors in Murine Islet Allografts: The Role for CCR2 and CCR5 signaling pathways. J Am Soc Neph 2004;1853-1861. PMID:15213273 Akalin E, Sehgal V, Ames S, Dikman S, Fotino M, Bromberg JS, Murphy B. Intravenous immunoglobulin treatment in a kidney transplant patient with chronic allograft nephropathy. Transplantation, 2005, 79:257-258. PMID:1566578 Schroppel B, Zhang N, Chen P, Chen D, Bromberg JS, Murphy B. The Role of Donor-Derived CCLl2/MCP-1 in Murine Islet Transplantation. J Am Soc Nephrol 2005: 16 (2): 444-51. PMID:156017 Weiping Zang, Safa Kalache, Marvin Lin, Bernd Schroppel, and Barbara Murphy. MHC Class II Mediated Apoptosis by a Non-Polymorphic MHC Class II Peptide Proceeds by Activation of Protein Kinase C. J Am Soc Nephrol 2005: 16:3661-3668. PMID:16221866 Enver Akalin, Rajani Dinavah, Steven Dikman, Graciela de Boccardo, Rex Friedlander, Bernd Schroppel, Vinita Sehgal, Jonathan S. Bromberg, Peter Heeger and Barbara Murphy. Transplant glomerulopathy may occur in the absence of donor-specific antibody and C4d staining. Clin J Am Soc Nephrol 2007: 2(6): 1261-7. PMID:17942771

9. Weiping Zang, Safa Kalache, Nan Zhang, Ana Maria WaagaGasser, Martin Grimm, M, Wayne Hancock, Bernd Schröppel, Barbara Murphy. Inhibition of the alloimmune response through the generation of regulatory T cells by a MHC class II-derived peptide. J Immunol 2008 181(11); 7499 – 506. PMID:19017939 10. Gurkan S, Dhillon N, Allam S, Montague T, Bromberg JS, Ames S, Lerner S, Ebcioglu Z, Nair V, Dinavahi R, Sehgal V, Schroppel B, Murphy B. Immune reconstitution following rabbit anti-thymocyte globulin. Am J of Transplantation 2010; 10:2132-2141. PMID:20883548 11. Stock P, Barin B, Murphy B, Hanto D, Diego JM, Light J, Davis C, Blumberg E, Simon C, Subramanian A, Harland R, Lyon GM, Brayman K, Slakey D, Shapiro R, Melancon R, Kumar A, Stosor V, Stablein DM and Roland ME. Kidney Transplant Outcomes in One Hundred and Fifty HIV-Infected Recipients. N Engl J Med 2010; 363:2004-2014. 12. Dhillon N, Walsh L, Krüger B, Mehrotra A, Ward SC, Godbold J, Radwan M, Schiano T, Murphy B, Schröppel B. (joint last author) Complement component C3 allotypes and outcomes in liver transplantation. Liver Transpl. 2010 Jan 26;16(2):198-203. 13. Dhillon N, Walsh L, Krüger B, Ward SC, Godbold JH, Radwan M, Schiano T, Murphy B, Schröppel B (Joint last Author). A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation. Hepatology 2010 Jul 53(1): 67-72. 14. Allam SR, Kruger B, YadavvA, Dhillon N, Walsh L, Ward CL, Mehrotra A, Schroppel B and Murphy B. The association of IL28B Polymorphism and Graft Survival in Patients with Hepatitis C undergoing Liver Transplantation. PLOS1 2013;8(1):e54854. Epub 2013 Jan 30. PMID:23382988

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15. Y. Luan, E. Mosheir, M. Menon, D. Wilson, C. Woytovich, J. Ochando, B. Murphy. Monocytic Myeloid Derived Suppressor Cells accumulate in Renal Transplant Patients and Mediate CD4+Foxp3+ Treg Expansion. Am J Transplantation 2013 Sep 18. doi: 10.1111/ajt.12461. [Epub ahead of print]. PMID:24103111

BIOGRAPHICAL SKETCH NAME Ochando, Jordi EDUCATION/TRAINING INSTITUTION AND LOCATION University of Alicante, Spain De Montfort University, Leicester, England Mount Sinai School of Medicine, New York A. Personal Statement My laboratory investigates the origin, development and immune regulatory function of myeloid derived suppressive cells (MDSC). As negative regulators of the immune response, MDSC represent a novel therapeutic approach for manipulating the immune system toward tolerance or immunity. Since MDSC have considerable relevance to the crucial problem as why a growing tumor cannot be rejected despite the recognition of tumor associated antigens, our laboratory investigates the immunological mechanisms of tumor acceptance mediated by MDSC, which can be exploited to prevent allograft rejection in transplantation. I have a broad background in transplant immunology with documented research experience. During my postdoctoral research at Mount Sinai School of Medicine, I published several manuscripts in high impact factor journals including two Nature Immunology manuscripts as fist author. Specifically, I investigated the suppressive function of regulatory T cells in transplantation using an experimental model of heart transplant in mice, and identified that alloantigen-presenting plasmacytoid dendritic cells participate Treg development and mediate tolerance. As principal investigator I laid the groundwork for my current research by identifying monocytic

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POSITION TITLE Assistant Professor of Medicine DEGREE B.Sc MPhil/PhD Postdoctoral

MM/YY 06-98 06-02 01-06

FIELD OF STUDY Biology Immunology Transplant Immunology

MDSC as critical components of the tolerogenic signature during the immune response to an allograft. This work was published in The Journal of Clinical Investigation in 2010. My laboratory is now focused in providing new insights into the mechanisms by which MDSC inhibit T cell responses and promote tolerance, and our current work it is being reviewed in the prestigious journal Immunity. We believe that understanding how myeloid derived suppressor cells inhibit T cell responses and promote regulatory T cell development in vivo will open new avenues for therapeutic intervention either by inhibiting their function (i.e. in cancer patients), or by enhancing their suppressive effects and promoting their expansion (i.e. in transplant recipients). As the scientific director of the Flow Cytometry Shared Research Facility at Mount Sinai School of Medicine I am also leading a team that provides state of the art technology and professional expertise to support planning of experiments, data acquisition, and analysis of flow cytometry experiments. Flow cytometry allows simultaneous multiparametric analysis and fluorescence activated cell sorting (FACS) of thousands of cells per second, which enables researchers to investigate complex cellular processes in a variety of models comprising healthy and disease states. It is therefore routinely used in the diagnosis of

health disorders, especially blood cancers, but has many other applications in both research and clinical practice. With this in mind, our mission is to provide the necessary instrumentation and knowledge for cell cytofluorimetric analysis and sterile sorting of specific cell types to the Immunology Institute investigators. B. Positions and Honors Positions and Employment: 2002-2006 Postdoctoral Fellow, Mount Sinai School of Medicine, NY 2006-2007 Academic Instructor, Mount Sinai School of Medicine, NY 2007-2010 Visiting Scientist, Mount Sinai School of Medicine, NY 2007-2010 Staff Scientist, Spanish Institutes of Health, Spain 2011- Assistant Professor, Mount Sinai School of Medicine, NY 2012- Scientific Director of Flow Cytometry SRF, Mount Sinai School of Medicine, NY Other Experience and Professional Memberships: 2007 Member of the Transplantation Society 2008 Member of the European Society for Organ Transplantation 2010 Member of the American Society of Transplantation Honors and Awards: 1998 De Montfort University PhD Fellowship 2002 Federation of Clinical Immunologists travel Award 2005 AST Young Investigator award 2006 AST International Investigator Award 2011 AST Basic Sciences Faculty Development Award

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C. Selected Peer-reviewed Publications (Selected from 23 peer-reviewed publications) 1. Gerold Bongers, Michelle E. Pacer, Thais H. Geraldino, Lili Chen, Zhengxiang He, Daigo Hashimoto, Glaucia C. Furtado, Jordi Ochando, Kevin A. Kelley, Jose C. Clemente, Miriam Merad, Harm van Bakel, and Sergio A. Lira. 2014. Interplay of host microbiota, genetic perturbations, and inflammation promote local development of intestinal neoplasms in mice. J Exp Med. In press. 2. Luan Y, Mosheir E, Menon MC, Wilson D, Woytovich C, Ochando J, Murphy B. Monocytic Myeloid-Derived Suppressor Cells Accumulate in Renal Transplant Patients and Mediate CD4(+) Foxp3(+) Treg Expansion. 2013. Am J Transplant.13(12):3123-31. PMID 24103111. 3. Stefano Ugel, Elisa Peranzoni, Giacomo Desantis Mariacristina Chioda, Steffen Walter, Toni Weinschenk, Jordi C. Ochando, Anna Cabrelle, Susanna Mandruzzato, and Vincenzo Bronte. 2012. Immune Tolerance to Tumor Antigens Occurs in a Specialized Environment of the Spleen. Cell Rep. 27;2(3):628-39, PMID:22959433. 4. Ochando JC and Chen SH. 2012. Myeloid-derived suppressor cells in transplantation and cancer. Immunol Res. 54(13):275-85, PMID:22535241. 5. Hashimoto D, Chow A, Greter M, Saenger Y, Kwan WH, Leboeuf M, Ginhoux F, Ochando JC, Kunisaki Y, van Rooijen N, Liu C, Teshima T, Heeger PS, Stanley ER, Frenette PS, Merad M. 2011. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J Exp Med. 208:1069-1082, PMID: 21536742, PMCID: PMC3092347. 6. Gehrie, E., Van der Touw, W., Bromberg, J.S., and Ochando, J.C. 2011. Plasmacytoid dendritic cells in tolerance. Methods Mol Biol. 677:127-147.PMID:20941607.

7. Boros, P., Ochando, J.C., Chen, S.H., and Bromberg, J.S. 2010. Myeloid-derived suppressor cells: natural regulators for transplant tolerance. Hum Immunol 71:1061-1066, PMID:20705113. 8. Rodriguez-Garcia, M., Boros, P., Bromberg, J.S., and Ochando, J.C. 2010. Immunotherapy with myeloid cells for tolerance induction. Curr Opin Organ Transplant.15:416-421, PMID:20616727. 9. Garcia MR, Ledgerwood L, Yang Y, Xu J, Lal G, Burrell B, Ma G, Hashimoto D, Li Y, Boros P, Grisotto M, van Rooijen N, Matesanz R, Tacke F, Ginhoux F, Ding Y, Chen SH, Randolph G, Merad M, Bromberg JS, and Ochando JC. 2010. Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice. J Clin Invest 120:2486-2496, PMID:20551515, PMCID:PMC2898596. 10. Zhang, N., Schroppel, B., Lal, G., Jakubzick, C., Mao, X., Chen, D., Yin, N., Jessberger, R., Ochando, J.C., Ding, Y., et al. 2009. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity 30:458-469, PMID:19303390, PMCID: PMC2737741. 11. Ledgerwood LG, Lal G, Zhang N, Garin A, Esses SJ, Ginhoux F, Merad M, Peche H, Lira SA, Ding Y, Yang Y, He X, Schuchman EH, Allende ML, Ochando JC, Bromberg JS. 2008. The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T

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lymphocytes into afferent lymphatics. Nat Immunol 9:4253, PMID:18037890. Randolph, G.J., Ochando, J., and Partida-Sanchez, S. 2008. Migration of dendritic cell subsets and their precursors. Annu Rev Immunol 26:293-316, PMID:18045026, Ginhoux F, Collin MP, Bogunovic M, Abel M, Leboeuf M, Helft J, Ochando J, Kissenpfennig A, Malissen B, Grisotto M, Snoeck H, Randolph G, Merad M. 2007. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J Exp Med 204:3133-3146, PMID:18086862, PMCID: PMC2150983. Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, Tacke F, Angeli V, Li Y, Boros P, Ding Y, Jessberger R, Trinchieri G, Lira SA, Randolph GJ, Bromberg JS. 2006. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 7:652-662, PMID:16633346. Ochando, J.C., Krieger, N.R., and Bromberg, J.S. 2006. Direct versus indirect allorecognition: Visualization of dendritic cell distribution and interactions during rejection and tolerization. Am J Transplant 6:2488-2496, PMID:16889597. Ochando, J.C., Yopp, A.C., Yang, Y., Garin, A., Li, Y., Boros, P., Llodra, J., Ding, Y., Lira, S.A., Krieger, N.R., et al. 2005. Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. J Immunol 174:6993-7005, PMID:15905542.

 

BIOGRAPHICAL SKETCH NAME Sampson , Hugh A. EDUCATION/TRAINING INSTITUTION AND LOCATION Hamilton College [Clinton, NY] S.U.N.Y. at Buffalo Medical School [Buffalo, NY] Children's Memorial Hosp [Northwestern; Duke University Medical Center [Durham, NC] Chicago, IL] A. Personal statement I am a pediatrician, pediatric allergist and immunologist. I have been involved in both basic and translational research on food allergy for nearly 30 years and have extensive experience in immunophenotyping. In basic studies by my group, we have developed and utilized murine models to investigate immune mechanisms of food-induced anaphylaxis and developed novel therapeutic strategies; e.g. engineered recombinant peanut protein vaccine. In human studies, we have investigated immune mechanisms of food-induced symptoms in children with atopic dermatitis, asthma, anaphylaxis and eosinophilic esophagitis, and developed novel approaches to better diagnose food allergy. We have characterized over 30 allergenic proteins in various food allergens, work that has contributed to a better understanding of allergic responses to food, better diagnostic assays and novel therapeutic approaches. I have conducted several clinical trials investigating therapeutic strategies to treat food allergy. I am the PI on the NIH-funded Consortium for Food Allergy Research [6 universities], which has investigated the use of egg oral immunotherapy, peanut sublingual immunotherapy, and rectal administration of a heatkilled E coli-containing re-engineered, recombinant peanut proteins (Ara h 1, 2 and 3). I currently direct the AADCRC   192

POSITION TITLE Professor of Pediatrics DEGREE B.A. M.D. Residency Fellowship

YEAR(s) 1971 1975 1978 1980

FIELD OF STUDY Biology Medicine Pediatrics Allergy/Immunology

program project on milk allergy, which has been investigating the administration of baked-milk products and milk oral immunotherapy with or without omalizumab. I have served on numerous expert panels, including the NIH Expert Panel on Food Allergy, and chaired an NIAID Expert Panel on the Guidelines for the Diagnosis & Management of Food Allergy. I have served as the Director of the General Clinical Research Center at Johns Hopkins and I am currently Director of Conduits, Mount Sinai’s CTSA. B. Positions and Honors Positions and Employment 1980 to 1986 Assistant to Associate Professor of Pediatrics, Duke Univ. School of Medicine 1983 to 1986 Associate Director, General Clinical Research Center, Duke University 1986 to 1991 Associate Professor of Pediatrics, Johns Hopkins Univ. School of Medicine 1988 to 1997 Director, Pediatrics Clinical Research Center, Johns Hopkins University 1991 to 1997 Professor of Pediatrics, Johns Hopkins University School of Medicine 1997 to present Professor of Pediatrics & Immunobiology, Mount Sinai School of Medicine

1997 to 2009 Chief, Div of Pediatric Allergy & Immunology, Mount Sinai School of Medicine 1999 to 2006; 2007 to 2009 Director, General Clinical Research Center, Mount Sinai School of Medicine 2006 to Present Dean for Translational Biomedical Sciences, Mount Sinai School of Medicine Other Experience and Professional Memberships 1981 to 2010 American Academy of Allergy Asthma & Immunology [Exec. Board: 1997-2000; 2005 2010; President: 2008 - 2009] 1985 to present Society of Pediatric Research 1987 to present American Association of Immunologists 1988 to 2011 American Academy of Pediatrics [Section on Allergy/Immunology Chairman: 1994-1996] 1/1994 to 6/1997 NIH Immunologic Sciences Study Section 1987-1992;1998-2008, 2009 – present Editorial Board - Journal Allergy and Clinical Immunology 1989 - present Assoc. Editor - Journal Pediatric Allergy & Immunology 2001- 2009 Editorial Board - International Arch Allergy Applied Immunology 1991- present Food Allergy & Anaphylaxis Network – Medical Director Honors 2002 International Award for Modern Nutrition 2003 Institute of Medicine, National Academy of Science 2004 American Pediatric Society 2004 Brett Ratner Award; American Academy of Pediatrics 2009 Jacobi Award; Mount Sinai School of Medicine 2001-2013 Castle Connolly America’s Top Doctors

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2014

AAAAI Distinguished Scientist Award

C. Selected from over 400 publications: 1. Wood RA, Sicherer SH, Burks AW, Grishin A, Henning AK, Lindblad R, Stablein D, Sampson HA. A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP123) for the treatment of peanut allergy. Allergy. 2013 Jun;68(6):803-8. PMID:23621498 2. Wood RA, Sicherer SH, Vickery BP, Jones SM, Liu AH, Fleischer DM, Henning AK, Mayer L, Burks AW, Grishin A, Stablein D, Sampson HA. The natural history of milk allergy in an observational cohort. J Allergy Clin Immunol. 2013 Mar;131(3):805-12. PMID:23273958 3. Vickery BP, Lin J, Kulis M, Fu Z, Steele PH, Jones SM, Scurlock AM, Gimenez G, Bardina L, Sampson HA, Burks AW. Peanut oral immunotherapy modifies IgE and IgG(4) responses to major peanut allergens. J Allergy Clin Immunol. 2013 Jan;131(1):128-134.e3. PMID:23199605 4. Fleischer DM, Burks AW, Vickery BP, Scurlock AM, Wood RA, Jones SM, Sicherer SH, Liu AH, Stablein D, Henning AK, Mayer L, Lindblad R, Plaut M, Sampson HA; Consortium of Food Allergy Research (CoFAR). 5. Sublingual immunotherapy for peanut allergy: A randomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol. 2013 Jan;131(1):119-127.e7. PMID:23265698 6. Pascal M, Konstantinou GN, Masilamani M, Lieberman J and Sampson HA. In silico prediction of Ara h 2 T cell epitopes in peanut-allergic children. Clin Exp Allergy 2013; 43: 116–127. 7. Burks AW, Jones SM, Wood RA, Fleischer DM, Sicherer SH, Lindblad RW, Stablein D, Henning AK, Vickery BP, Liu AH, Scurlock AM, Shreffler WG, Plaut M, Sampson HA;

 

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Consortium of Food Allergy Research (CoFAR). Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012 Jul 19;367(3):233-43. PMID: 22808958 Fleischer DM, Perry TT, Atkins D, Wood RA, Burks AW, Jones SM, Henning AK, Stablein D, Sampson HA, Sicherer SH. Allergic reactions to foods in preschool-aged children in a prospective observational food allergy study. Pediatrics. 2012 Jul;130(1):e25-32. Epub 2012 Jun 25. PMID: 22732173 Lieberman JA, Huang FR, Sampson HA, Nowak-Węgrzyn A. Outcomes of 100 consecutive open, baked-egg oral food challenges in the allergy office. J Allergy Clin Immunol. 2012 Jun;129(6):1682-4.e2. PMID: 22657409 Srivastava KD, Bardina L, Sampson HA, Li XM. Efficacy and immunological actions of FAHF-2 in a murine model of multiple food allergies. Ann Allergy Asthma Immunol. 2012 May;108(5):351-358.e1. PMID: 22541407 Leonard SA, Sampson HA, Sicherer SH, Noone S, Moshier EL, Godbold J, Nowak-Węgrzyn A. Dietary baked egg accelerates resolution of egg allergy in children. J Allergy Clin Immunol. 2012 Aug;130(2):473-480.e1. PMID: 22846751 Ford LS, Bloom KA, Nowak-Węgrzyn AH, Shreffler WG, Masilamani M, Sampson HA. Basophil reactivity, wheal size, and immunoglobulin levels distinguish degrees of cow's milk tolerance. J Allergy Clin Immunol. 2013 Jan;131(1):180186.e3. PMID:22819512 Patil SP, Wang J, Song Y, Noone S, Yang N, Wallenstein S, Sampson HA, Li XM. Clinical safety of Food Allergy Herbal Formula-2 (FAHF-2) and inhibitory effect on basophils from

Other publications: 19. Sampson HA. Peanut Oral Immunotherapy: Is It Ready for Clinical Practice? J Allergy Clin Immunol: In Practice. 2013; 1:15-21. PMID:24229817   194

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patients with food allergy: Extended phase I study. J Allergy Clin Immunol. 2011;128(6):1259-1265.e2. PMID:21794906 Kim JS, Nowak-Węgrzyn A, Sicherer SH, Noone S, Moshier EL, Sampson HA. Dietary baked milk accelerates the resolution of cow's milk allergy in children. J Allergy Clin Immunol. 2011 Jul;128(1):125-131.e2. PMID: 21601913 Sicherer SH, Wood RA, Stablein D, Burks AW, Liu AH, Jones SM, Fleischer DM, Leung DY, Grishin A, Mayer L, Shreffler W, Lindblad R, Sampson HA. Immunologic features of infants with milk or egg allergy enrolled in an observational study (Consortium of Food Allergy Research) of food allergy. J Allergy Clin Immunol. 2010 May;125(5):1077-1083.e8. PMID: 20451041 Savilahti EM, Rantanen V, Lin JS, Karinen S, Saarinen KM, Goldis M, Mäkelä MJ, Hautaniemi S, Savilahti E, Sampson HA. Early recovery from cow's milk allergy is associated with decreasing IgE and increasing IgG4 binding to cow's milk epitopes. J Allergy Clin Immunol. 2010 Jun;125(6):13151321.e9. PMID: 20462631 Lin J, Bardina L, Shreffler WG, Andreae DA, Ge Y, Wang J, Bruni FM, Fu Z, Han Y, Sampson HA. Development of a novel peptide microarray for large-scale epitope mapping of food allergens. J Allergy Clin Immunol. 2009 Aug;124(2):31522, 322.e1-3. PMID: 19577281 Nowak-Wegrzyn A, Bloom KA, Sicherer SH, Shreffler WG, Noone S, Wanich N, Sampson HA. Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol. 2008 Aug;122(2):342-7.

20. Berin MC, Sampson HA. Mucosal immunology of food allergy. Curr Biol. 2013 May 6; 23(9):R389-400. PMID:23660362 21. Berin MC, Sampson HA. Food allergy: an enigmatic

epidemic. Trends Immunol. 2013 Aug; 34(8):390-7. PMID:23648309 22. Leung DYM, Sampson HA, Yunginger JW, Burks AW, Schneider LC, Wortel CH, Davis FM, et al. Effect of anti-IgE therapy (TNX-901) in patients with severe peanut allergy. N Engl J Med 2003; 348:986-93. 23. Li XM, Srivastava K, Grishin A, Huang CK, Schofield BH. AW Burks, Sampson HA. Persistent protective effect of heatkilled Escherichia coli producing "engineered," recombinant peanut proteins in a murine model of peanut allergy. J Allergy Clin Immunol 2003; 112(1):159-67. 24. Sicherer SH, Wood RA, Stablein D, Lindblad R, Burks AW, Liu AH, Jones SM, Fleischer DM, Leung DY, Sampson HA. Maternal consumption of peanut during pregnancy is associated with peanut sensitization in atopic infants. J Allergy Clin Immunol. 2010 Dec;126(6):1191-7. 25. Sampson HA, Gerth van Wijk R, Bindslev-Jensen C, Sicherer S, Teuber SS, Burks AW, Dubois AE, Beyer K, Eigenmann PA, Spergel JM, Werfel T, Chinchilli VM. Standardizing doubleblind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol. 2012 Dec;130(6):1260-74.

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BIOGRAPHICAL SKETCH NAME Sealfon, Stuart Charles EDUCATION/TRAINING INSTITUTION AND LOCATION Princeton University Columbia University Mount Sinai School of Medicine A. Personal Statement. My group applies systems biology approaches to immunological, neurobiological and endocrinological research questions. B. Positions and Honors. 1982-1983 Medical Internship, Massachusetts General Hospital, Harvard Medical School. 1983-1986 Neurology Residency, Massachusetts General Hospital, Harvard Medical School 1986-1988 Postdoctoral Fellow, Neurobiology, Mount Sinai School of Medicine 1988-1993 Assistant Professor, Neurobiology and Neurology, Mount Sinai School of Medicine 1993-1997 Associate Professor, Neurobiology and Neurology, Mount Sinai School of Medicine 1997-2001 Associate Professor with Tenure, Neurobiology and Neurology, Mount Sinai School of Medicine 2001- Professor, Neurology, Neurobiology, Pharmacology and Biological Sciences, Mount Sinai 2002-2009 Director of Research, Neurology, Mount Sinai School of Medicine 2002-2009 Saunders Professor of Neurology, Mount Sinai School of Medicine 2003-2009 Director, Microarray, PCR and Bioinformatics Shared Research Facility 196

POSITION TITLE Professor and Chairman DEGREE A.B. M.D.

MM/YY 1978 1982 1988

FIELD OF STUDY Comparative Literature Medicine Neurobiology

2006-2009 Director, Center for Translational Systems Biology 2007-2009 Director, Center for Genomics, Proteomics and Bioinformatics 2009- Glickenhaus Professor of Neurology, Mount Sinai School of Medicine 2009- Chair, Department of Neurology, Mount Sinai School of Medicine High Honors 1978, Phi Beta Kappa 1978, Princeton Comparative Literature Thesis Award 1978, Sciarra Neurology Prize 1982, Sandoz Neuroscience Research Award 1982, Physician Scientist Award 1989, Board Certification in Neurology 1991, Board Member Endocrine Journal (1993-2000), Board Member Molecular Endocrinology (1998-2001), Biochemical Endocrinology Study Section (DDK), Center for Scientific Review, 1998-2002. Special Emphasis Panel (NIDA), Center for Scientific Review 1999-2001. Assistant Editor Mount Sinai Journal of Medicine (assistant editor, 1994-2006), Reviewing Editor Biochemical Journal (2002-2010). NARSAD distinguished investigator award 2010. C. Selected Peer-reviewed Publications. 1. Mitchell, R, McCulloch, D, Lutz, E, Johnson, M, MacKenzie, C, Fennell, M, Fink, G, Zhou, W, and Sealfon, SC, Rhodopsinfamily receptors associate with small G proteins to activate phospholipase D. Nature, 1998. 392(6674)411-4.

2. Gonzalez-Maeso, J, Ang, RL, Yuen, T, Chan, P, Weisstaub, NV, Lopez-Gimenez, JF, Zhou, M, Okawa, Y, Callado, LF, Milligan, G, Gingrich, JA, Filizola, M, Meana, JJ, and Sealfon, SC, Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature, 2008. 452(7183): p. 93-7. PCMID: 2743172 3. Borderia, AV, Hartmann, BM, Fernandez-Sesma, A, Moran, TM, and Sealfon, SC, Antiviral-activated dendritic cells: a paracrine-induced response state. Journal of immunology, 2008. 181(10): p. 6872-81. 4. Shimoni, Y, Fink, MY, Choi, SG, and Sealfon, SC, Plato's cave algorithm: inferring functional signaling networks from early gene expression shadows. PLoS Comput Biol, 2010. 6(6): p. e1000828.PCMID: 2891706 5. Patil, S, Pincas, H, Seto, J, Nudelman, G, Nudelman, I, and Sealfon, SC, Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase. BMC systems biology, 2010. 4: p. 137. 6. Seto, J, Qiao, L, Guenzel, CA, Xiao, S, Shaw, ML, Hayot, F, and Sealfon, SC, Novel Nipah virus immune-antagonism strategy revealed by experimental and computational study. J Virol, 2010. 84(21): p. 10965-73. PCMID: 2953155 7. Nudelman, G, Ge, Y, Hu, J, Kumar, M, Seto, J, Duke, JL, Kleinstein, SH, Hayot, F, Sealfon, SC, and Wetmur, JG, Coregulation mapping based on individual phenotypic variation in response to virus infection. Immunome research, 2010. 6: p. 2. 8. Qiao, L, Phipps-Yonas, H, Hartmann, B, Moran, TM, Sealfon, SC, and Hayot, F, Immune response modeling of interferon beta-pretreated influenza virus-infected human dendritic cells. Biophysical journal, 2010. 98(4): p. 505-14. 9. Zaslavsky, E, Hershberg, U, Seto, J, Pham, AM, Marquez, S, Duke, JL, Wetmur, JG, Tenoever, BR, Sealfon, SC, and

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Kleinstein, SH, Antiviral response dictated by choreographed cascade of transcription factors. J Immunol, 2010. 184(6): p. 2908-17. 2856074. Ge, Y and Sealfon, SC, flowPeaks: a fast unsupervised clustering for flow cytometry data via K-means and density peak finding. Bioinformatics, 2012. 28(15): p. 2052-8. Braun, DA, Fribourg, M, and Sealfon, SC, Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation. The Journal of biological chemistry, 2013. 288(5): p. 2986-93. Zaslavsky, E, Nudelman, G, Marquez, S, Hershberg, U, Hartmann, BM, Thakar, J, Sealfon, SC, and Kleinstein, SH, Reconstruction of regulatory networks through temporal enrichment profiling and its application to H1N1 influenza viral infection. BMC Bioinformatics, 2013. 14 Suppl 6: p. S1. Hartmann, BM, Li, W, Jia, J, Patil, S, Marjanovic, N, MartinezRomero, C, Albrecht, RA, Hayot, F, Garcia-Sastre, A, Wetmur, JG, Moran, TM, and Sealfon, SC, Mouse dendritic cell (DC) influenza virus infectivity is much lower than that for human DCs and is hemagglutinin subtype dependent. Journal of virology, 2013. 87(3): p. 1916-8. Tabbaa, OP, Nudelman, G, Sealfon, SC, Hayot, F, and Jayaprakash, C, Noise propagation through extracellular signaling leads to fluctuations in gene expression. BMC systems biology, 2013. 7: p. 94. Hartmann, BM, Marjanovic, N, Nudelman, G, Moran, TM, and Sealfon, SC, Combinatorial cytokine code generates antiviral state in dendritic cells. Frontiers in immunology, 2014. 5: 73.

BIOGRAPHICAL SKETCH NAME Sikora, Andrew, Gregory EDUCATION/TRAINING INSTITUTION AND LOCATION Yale University, New Haven, CT Albert Einstein College of Medicine, Bronx, NY Albert Einstein College of Medicine, Bronx, NY A. Personal Statement As a fellowship-trained surgical oncologist and immunologist with experience in both basic laboratory science and clinical trials, my unique portfolio of expertise provides the background necessary to mentor graduate students with an interest in translational research. I have extensive training in, and publications relating to, head and neck cancer, basic immunology, inflammation, cancer immunotherapy, and translational cancer research. I am the PI of multiple clinical trials, including trials related to HPV-mediated squamous cell carcinoma, and immunology of head and neck cancer. I also run a basic/translational laboratory focused on understanding mechanisms of tumor-induced inflammation and immunosuppression and harnessing targeted therapy approaches to improve anti-cancer immunotherapy. Mentoring graduate and medical students and postdoctoral fellows has been one of the great pleasures of my career thus far, and I am proud of the many students who have won research prizes and obtained competive grants and fellowships to support their work - including awards from the NCI, the German Cancer Aid Foundation, and the Doris Duke and Howard Hughes research foundations. B. Positions and Honors Positions and Employment 198

POSITION TITLE Assistant Professor DEGREE BS MD PhD

MM/YY

FIELD OF STUDY Biology Medicine Microbiology and Immunology

9/2008 - present Assistant Professor and Director of Head and Neck Translational Research, Departments of Otolaryngology/Head and Neck Surgery, Immunology, Oncologic Sciences, Dermatology, Mount Sinai Medical School, New York, NY USA 6/2014 Associate Professor with Tenure and Vice Chair for Research, Department of Otolaryngology, Baylor College of Medicine, Houston, TX (PENDING) 6/2014 Co-Director, Head and Neck Cancer Program, Baylor College of Medicine, Houston, TX (PENDING) Other Experience and Professional Memberships 1996 Qualified to work with biosafety level 3 pathogens, (AECOM, Bronx, NY) 1999 - present Member, Alpha Omega Alpha Medical Honor Society 2000 - 2005 Associate Fellow, the New York Academy of Medicine 2001 - present Member, American Academy of Otolaryngology (AAO) 2008 - present Member, American Head and Neck Society 2009 - present American Academy of Otolaryngology CORE grants review committee

2009 - 2011 Member, Mount Sinai School of Medicine Institutional Review Board (IRB) 2009 - 2010 Member, Mount Sinai School of Medicine Graduate Curriculum Committee 2009 – present Member, MSSM Head and Neck Cancer Disease Focus Group 2009 – present Small group discussion leader, MSSM Medical School Immunology Course 2010 – present Lecturer, MSSM Graduate School Immunology Course 2011 – present Co-chair, MSSM Head and Neck Cancer Disease Focus Group 2011 – present Ad-hoc reviewer, MSSM cancer Protocol Review and Monitoring Committee (PRMC) 2013-present Member, Cancer Vaccine Consortium (CVC) 2014 Reviewer, Tisch Cancer Center Developmental Research Awards, Icahn School of Medicine at Mount Sinai Ongoing Reviewer for peer-reviewed journals: Vaccine, Journal of Immunotherapy, Laryngoscope, Otolaryngology-Head and Neck Surgery, Annals of Otolaryngology, Head and Neck, Infectious Agents and Cancer, Oral Oncology, Cancer Selected Honors (selected from 16) 2000 First Place Award for Distinguished Performance in Research, The Associated Medical Schools of New York Research Competition 2003 First place award for research, New York Head and Neck Society 2004 Second place award for research, Triological Society Eastern Section Meeting 2007 National Cancer Institute Scholarship Award for Keystone Symposium: The Potent New Anti-Tumor Immunotherapies

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2008 American Head and Neck Society Robert Maxwell Byers Award for best clinical paper, AHNS 7th International Conference 2009 Damon Runyon-Rachleff Innovation Award, SemiFinalist C. Selected Peer-reviewed Publications (of 52) 1. A. Sikora, J. Liu, C. Brosnan, G. Buell, I. Chessel, B. Bloom. Purinergic Signaling Regulates Radical-Mediated Bacterial Killing Mechanisms In Macrophages Through A P2x7Independent Mechanism. Journal of Immunology Cutting Edge 1999; 163: 558-561. 2. J. Liu, G. John, A. Sikora, S. Lee, C. Brosnan. Nuclear FactorKB Activation By Interleukin-1 By Human Fetal Astrocytes Is Regulated By Purinergic Receptors. Journal of Neuroscience 2000. 20:5292-9. 3. M. Kuriakose, W. Chen, Z. He, A. Sikora, P. Zhang, Z. Zhang, W. Qiu, D. Hsu, C. McMunn-Coffran, S. Brown, E. Elango, M. DeLacure, F. Chen. Selection And Validation Of Differentially-Expressed Genes In Head And Neck Cancer. Cellular and Molecular Life Science 2004. 61:1372-1383. 4. Y. Liu, Y Lou, G. Lizee, H. Qin, S Liu, B. Rabinovich, G. Kim, Y. Wang, Y. Ye, A. Sikora, W. Overwijk, Y. Liu, G. Wang, P. Hwu Plasmacytoid Dendritic Cells Induce NK CellDependent Tumor Antigen-Specific T-Cell Cross-Priming And Tumor Regression. Journal of Clinical Investigation 2008; 118:1165-1175. 5. A. Sikora, N. Jaffarzad, Y. Hailemichael, A. Gelbard, S. Stonier, K. Schluns, L. Frasca, Y. Lou, C. Liu, H. Andersson, P. Hwu, W. Overwijk. Interferon-α Enhances Peptide VaccineInduced CD8+ T Cell Numbers, Effector Function, And AntiTumor Activity. Journal of Immunology 2009; 182: 73987407.

6. H. Vu, A. Sikora, S. Fu, J. Kao. HPV-Induced Oropharyngeal Cancer, Immune Response, And Response To Therapy. Cancer Letters 2009; 288(2):149-155. 7. J. Kao, A. Sikora, S. Fu. Dual EGFR And COX-2 Inhibition As A Novel Approach To Targeting Head And Neck Squamous Cell Carcinoma. Current Cancer Drug Targets 2009; 9:931937. 8. A. Sikora, A. Gelbard, M. Davies, D. Sano, S. Ekmekcioglu, J. Kwon, Y. Hailemichael, P. Jayaraman, J. Myers, E. Grimm, W. Overwijk. Targeted Inhibition Of Inducible Nitric Oxide Synthase Inhibits Growth Of Human Melanoma In Vivo And Synergizes With Chemotherapy. Clinical Cancer Research 2010; 16(6): 1834-44. 9. L. Morris, A. Sikora, S. Patel, R. Hayes, I. Ganley. Second Primary Cancers After An Index Head And Neck Cancer: Subsite-Specific Trends In The Era Of HPV-Associated Oropharyngeal Cancer. Journal of Clinical Oncology 2011; 29(6):739-46. 10. L. Morris, A. Sikora, R. Hayes, S. Patel, I. Ganly. Anatomic Sites At Elevated Risk Of Second Primary Cancer After An Index Head And Neck Cancer. Cancer Causes and Control 2011; 22(5):671-679. 11. P. Jayaraman, F. Parikh, E. Lopez-Rivera, D. Cannan, Y. Hailemichael, W. Overwijk, S.H. Chen, A. Sikora. TumorExpressed Inducible Nitric Oxide Synthase Controls Induction Of Functional Myeloid-Derived Suppressor Cells Through Modulation Of Vascular Endothelial Growth Factor Release. Journal of Immunology 2012; 188:5365-5376. 12. R. Anvekar, J. Asciolla, E. Rivera, K. Floros, R. Elkholi, G. Morven-Belbin, A. Sikora*, J. Chipuk*. Sensitization To The Mitochondrial Pathway Of Apoptosis Augments Melanoma Tumor Cell Responses To Chemotherapeutic Regimens. Cell

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Death and Disease 2012; 3:e420. doi: 10.1038/cddis.2012.161. *Co-corresponding authors. 13. K. Jain, A. Sikora, S. Baxi, L. Morris. Synchronous cancers in patients with head and neck cancer: risks in the era of human papillomavirus-associated oropharyngeal cancer. Cancer 2013; (Epub ahead of print). 14. J. Yang, R. Zhang, G. Lu, Y. Shen, C. Zhu, M. Cui, W. Wang, P. Arnaboldi, L. Peng, M. Tang, M. Gupta, C. Qi, P. Jayaraman, H. Zhu, B. Jiang, S. Chen, J. He, A. Ting, V. Kuchroo, H. Morse, K. Ozato, A. Sikora, H. Xiong. T Cell-Derived Inducible Nitric Oxide Synthase Switches Off Th17 Cell Differentiation. 2013 Journal of Experimental Medicine (in press). 15. E. Lopez-Rivera, P. Jayaraman, F. Parikh, M. A. Davies, S. Ekmekcioglu, S. Izadmehr, D.R. Milton, J.E. Chipuk, E. Grimm, Y. Estrada, J. Aguirre-Ghiso, A. Sikora. Inducible nitric oxide synthase (iNOS) drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2. (in press – Cancer Research)

BIOGRAPHICAL SKETCH NAME Ting, Adrian T. EDUCATION/TRAINING INSTITUTION AND LOCATION Luther College, Decorah, IA Mayo Graduate School, Rochester, MN Massachusetts General Hospital, Boston, MA A. Personal Statement My lab is interested in the role of ubiquitination and how this post-translational modification affects cellular survival and death, as well as inflammatory signaling pathways. One focus of our studies is the role played by ubiquitination of the TNFR1 signaling molecule RIP1. We made the discovery that noncanonical K63-linked polyubiquitination of RIP1, or the lack thereof, determines whether cell survival or apoptotic cell death ensues in response to TNF. Thus, ubiquitination of RIP1 serves to function as an early cell death checkpoint in TNF signaling. More recently, we discovered that ubiquitination also has a significant role in regulating a novel form of cell death that is caspaseindependent known as necroptosis or programmed necrosis. Specifically, we made the observation that Caspase 8 has a prosurvival function (contrary to its well established role in causing apoptosis) by inhibiting necroptosis via the cleavage and degradation of CYLD. CYLD is a tumor suppressor and is a deubiquitinating enzyme that preferentially removes noncanonical K63-linked polyubiquitin chains from target proteins including RIP1. Removal of ubiquitin chains from RIP1 by CYLD is required for necrotic cell death to occur. Apoptotic cell death is generally thought of to be anti-inflammatory whereas necrotic cell death is thought of to be inflammatory. Since dysregulation of TNF underlies multiple inflammatory diseases, development 201

POSITION TITLE Associate Professor, Immunology Institute DEGREE B.A. Ph.D. Post-doc

MM/YY 1987-1989 1989-1994 1994-1999

FIELD OF STUDY Biology Immunology Molecular Biology

of pharmacological agents that disrupt the function of CYLD, RIP1 ubiquitination, or other proximal elements of this cell death pathway, may be useful to modulate the pro-inflammatory effects of TNF. Our goal is to thoroughly characterize the regulation of this early cell death checkpoint at the molecular level so that we can rationally design drugs to disrupt this checkpoint for therapeutic purposes in inflammatory diseases. B. Positions and Honors Research/Professional Experience 1988 Summer Student Research, The Jackson Laboratory, Bar Harbor, ME 1989 Laboratory Technician, Mayo Clinic, Rochester, MN 1989-1994 Predoctoral Research, Dept. of Immunology, Mayo Clinic, Rochester, MN. Advisor: Dr. Paul Leibson. 1994-1999 Postdoctoral Research, Dept. of Molecular Biology, Massachusetts General Hospital, Dept. of Genetics, Harvard Medical School, Boston, MA. Advisor: Dr. Brian Seed. 1999-2007 Assistant Professor, Immunobiology Center, Mt. Sinai School of Medicine, New York, NY. 2007-2008 Assistant Professor, Department of Medicine, Division of Clinical Immunology, Mt. Sinai School of Medicine, New York, NY.

2009-present Associate Professor, Department of Medicine, Division of Clinical Immunology, Mt. Sinai School of Medicine, New York, NY. 2007-present Member, Immunology Institute, Mt. Sinai School of Medicine, New York, NY. 2004-2007 Co-director, Molecular, Cellular, Biochemical and Developmental Sciences (MCBDS) graduate training area. 2007-present Co-director, Immunology (IMM) graduate training area. Honors 1987-1989 International Student Scholarship, Luther College, Decorah, IA 1987-1989 Dean’s List, Luther College, Decorah, IA 1988-1989 Dean’s Scholarship, Luther College, Decorah, IA 1988 Summer Student Research Scholarship, The Jackson Laboratory, Bar Harbor, ME 1995-1998 Postdoctoral Fellowship, Cancer Research Institute, New York, NY 1996 Young Investigator Travel Grant, Programmed Cell Death, AACR Special Conference, Bolton Landing, NY 2003 AAI Junior Faculty Travel Award, AAI 2003, Denver, CO. 2003 Mount Sinai Graduate School Excellence in Teaching Award. 2007 The Irma T. Hirschl/Monique Weill Caulier Trusts Award. Other Experience and Professional Membership 2000-present American Association of Immunologist 2003-2010 Ad Hoc Reviewer, NIH ALY & CMI-A Study Sections 2005 Ad Hoc Reviewer. NIH ZRG1 special emphasis Study Section

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2009-present Ad Hoc Reviewer, CCFA Research Fellowship Study Section (Mar 2009 - Mar 2010) 2011-present Permanent Member, NIH CMI-A Study Section C. Selected Peer-reviewed Publications (Selected from 27 peer-reviewed publications) Relevant to the current application 1. O’Donnell, M.A., Legarda-Addison, D, Skountzos, P., Yeh, W.C., and Ting, A. T. Ubiquitination of RIP1 regulates an NFkB-independent cell death switch in TNF signaling. Curr. Biol. 17:418-424 (2007). PMCID: PMC1868513 2. Legarda-Addison, D.*, Hase, H.*, O’Donnell, M. A., and Ting, A. T. NEMO/IKKγ regulates an early NF-κB-independent cell death checkpoint during TNF signaling. Cell Death & Diff. 16:1279-1288 (2009). *Equal contribution. PMCID: PMC2728158 3. O’Donnell, M. A., and Ting, A. T. Chronicle of a death foretold: dual sequential cell death checkpoints in TNF signaling. Cell Cycle. 9:1065-1071 (2010). PMID: 20237426 4. O’Donnell, M. A., and Ting, A. T. RIP1 comes back to life as a cell death regulator in TNFR1 signaling. FEBS J. 278:877-887 (2011). PMCID: PMC3051001. 5. O’Donnell, M. A.*, Perez-Jimenez, E.*, Oberst, A., Ng., A., Massoumi, R., Xavier, R., Green, D.R., and Ting, A. T. Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol. 13:1437-1442 (2011). *Equal contribution. PMCID:PMC3229661. 6. O’Donnell, M. A.*, Hase, H.*, Legarda, D., and Ting, A. T. NEMO inhibits programmed necrosis in an NFkappaBindependent manner by restraining RIP1. PLoS One. 7(7):e41238 (2012). *Equal contribution. PMCID: PMC3406058.

Additional recent publications 1. Ting, A. T.*, Pimentel-Muinos, F. X.*, and Seed, B. RIP mediates tumor necrosis factor receptor 1 activation of NFκB but not FAS/APO-1-initiated apoptosis. EMBO J. 15:61896196 (1996). *Equal contribution. PMCID: PMC452440 2. Jiang, C., Ting, A.T., and Seed, B. PPARγ agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82-86 (1998). PMID: 9422509 3. He, K-L. and Ting, A. T. A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. Mol. Cell. Biol. 22: 6034-6045 (2002). PMCID: PMC133997 4. He, K-L. and Ting, A. T. Essential role for IKKγ/NEMO in TCRinduced IL-2 gene expression in Jurkat T cells. Eur. J. Immunol. 33:1917-1924 (2003). PMID:12884855 5. Goodkin, M. L., Ting, A. T., and Blaho, J. A. NF-κB is required for apoptotis prevention during HSV-1 infection. J. Virol. 77:7261-7280 (2003). PMCID: PMC164802 6. Zhang, Y., Ting, A. T., Marcu, K. B., and Bliska, J. B. Inhibition of MAPK and NF-κB pathways is necessary for rapid apoptosis in macrophages infected with Yersinia. J. Immunol. 174: 7939-7949 (2005). PMID: 15944300 7. Yang, M., Hase, H., Legarda-Addison, D., Varughese, L., Seed, B., and Ting, A. T. BCMA, the receptor for APRIL and BAFF, induces antigen presentation in B cells. J. Immunol. 175: 28142824 (2005). PMID: 16116167 8. Legarda-Addison, D, and Ting, A. T. Negative regulation of TCR signaling by NF-kB2/p100. J. Immunol. 178:7767-7778 (2007). PMID: 17548614 9. Friedman, C. S.*, O’Donnell, M. A.*, Legarda-Addison, D, Ng, A., Cardenas, W. B., Yount, J. S., Moran, T. M., Basler, C. F., Komuro, A., Horvath, C. M., Xavier, R., and Ting, A. T. The 203

tumour suppressor CYLD is a negative regulator of RIG-Imediated anti-viral response. EMBO Reports. 9:930-936 (2008). *Equal contribution. PMCID: PMC2529351 10. Lu, J., McEachern, D., Sun, H., Bai, L., Peng, Y., Qiu, S., Miller, R., Liao, J., Yi, H., Liu, M., Bellail, A., Hao, C., Sun, Y.-H., Ting, A. T., and Wang, S. Therapeutic potential and molecular mechanism of a novel, potent, nonpeptide, Smac mimetic SM-164 in combination with TRAIL for cancer treatment. Mol Cancer Ther. 10:902-914 (2011). PMCID: PMC3091962.

 

BIOGRAPHICAL SKETCH NAME Tomer, Yaron EDUCATION/TRAINING INSTITUTION AND LOCATION Columbia University, New York, N.Y. (transferred to Tel-Aviv University) Sackler School of Medicine, Tel-Aviv University, Sackler Israel School of Cont. Med. Education Tel-Aviv Univ. POSITIONS AND HONORS Positions and Employment 1983-1984 Internship, Beilinson Medical Center, Israel 1984-1988 Physician, IDF. 1987-1991 Visiting Researcher, Department of cell biology, Weizmann Inst. of Science, Israel. 1989-1993 Medical Residency, Sheba Medical Center, Israel. 7/91-4/92 Visiting Research Fellow, Div. of Endocrinology, Mount Sinai Med. Center. N.Y. 1993-1994 Attending physician, Department of Medicine, Sheba Medical Center, Israel. 1994-1995 Lecturer in Internal Medicine, Sackler School of Medicine, Tel-Aviv University, Israel. 1994-1996 Fellow, Division of Endocrinology & Metabolism, Mount Sinai Medical Center, N.Y. 1996-1997 Resident, Department of Medicine, Mount Sinai Medical Center, N.Y. 1997-2003 Assistant Professor, Mount Sinai School of Medicine, New York, N.Y. 2003-2005 Associate Professor, Mount Sinai School of Medicine, New York, N.Y.   204

POSITION TITLE Professor, Chief, Division of Endocrinology, Department of Medicine, Mount Sinai School of Medicine, N.Y., N.Y. DEGREE N/A M.D. Master

YEAR(s) 19761977 June 1985 June 1994

FIELD OF STUDY Pre-Medicine Medicine Internal Medicine

2005-2009 Professor, University of Cincinnati College of Medicine; Staff Physician Cincinnati VAMC, Cincinnati OH. 2009-2011 Professor, Vice Chairman of Medicine for Research, Mount Sinai School of Medicine, NY. 2009 to present Staff Physician, James J Peters VAMC, N.Y. 2011 to present Professor, Chief Division of Endocrinology, Mount Sinai School of Medicine, N.Y. Other Experience and Professional Memberships 1997-2005 Member, Steering Committee, HBDI, Thyroid Diseases Resource, Philadelphia, PA. Sept. 2002 Member, Agency for Toxic Substances & Disease Registry panel on autoimmunity 2009-2010 Member, Organizing Committee, 7TH International Congress on Autoimmunity. 2009–2011 Member, Integrative and Clinical Endocrinology and Reproduction Study Section (ICER), Center for Scientific Review, NIH. Awards and Honors 1977-1978 Dean’s List, Columbia College, New York, N.Y. 1985 M.D. awarded MAGNA CUM LAUDE, Sackler School of Medicine, Tel-Aviv University.

1991 Al-Zohar basic research training Award, Sheba Medical Center. 1992 Prochobnik Award for research on the biology of aging, Israel Gerontological Society. 1993-1994 Young Researcher Award, Israel Ministry of Health, Chief Scientist office. 1997 American Thyroid Association Research Award. 2001 Fellow, American College of Physicians. 2002 Mount Sinai Endocrinologist of the year award, Dept. of Medicine, Mt. Sinai School of Medicine. 2003 Van Meter award and lectureship, American Thyroid Association. 2005 Member, American Society for Clinical Investigation. 2005-2009 Millennium Scholar, University of Cincinnati, Cincinnati, OH. 2007 Winner, Abbott Award for Thyroid Research, 89TH Endocrine Society meeting, Toronto, 6/2007. 2011 Lillian and Henry M. Stratton endowed chair in Molecular Medicine, Mt Sinai School of Medicine. 2011 Annual Farahe Maloof Memorial Lecture. Mass. General Hospital, Boston, MA, 12/2011. 2012 The Boris Catz Lecture. Cedars Sinai Hospital, Los Angeles, CA, 2/2012. 2013 Member, Interurban Clinical Club, founded by Sir William Osler in 1905. SELECTED PEER-REVIEWED PUBLICATIONS: (Selected from 168 publications) 1. Tomer Y, Ban Y, Concepcion E, Barbesino G, Villanueva R, Greenberg DA, Davies TF. Common and unique susceptibility loci in Graves and Hashimoto diseases:

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Results of whole-genome screening in a data set of 102 multiplex families. Am J Hum Genet 2003; 73: 736-747. Ban Y, Greenberg DA, Concepcion E, Skrabanek L, Villanueva R, Tomer Y. Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci USA 2003; 100: 15119-15124. Golden B, Levin L, Ban Y, Concepcion E, Greenberg DA, Tomer Y. Genetic analysis of families with autoimmune diabetes and thyroiditis: Evidence for common and unique genes. J Clin Endocrinol Metab 2005; 90: 4904-4911. Menconi F, Monti MC, Greenberg DA, Oashi T, Osman R, Davies TF, Ban Y, Jacobson EM, Concepcion ES, Li CW, Tomer Y. Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice. Proc Natl Acad Sci USA 2008; 105: 14034-14039. PMCID: PMC2544574. Vieland VJ, Huang Y, Bartlett C, Davies TF, Tomer Y. A multilocus model of the genetic architecture of autoimmune thyroid disorder, with clinical implications. Am J Hum Genet 2008; 82: 1349-1356. PMCID: PMC2427261. Huber A, Menconi F, Corather S, Jacobson EM, Tomer Y. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: From epidemiology to mechanisms. Endocr Rev 2008; 29: 697-725. PMCID: PMC2583387. Jacobson EM, Yang H, Menconi F, Wang R, Osman R, Skrabanek L, Li CW, Fadlalla M, Gandhi A, Chaturvedi V, Smith EP, Schwemberger S, Osterburg A, Babcock GF, Tomer Y. Employing a recombinant HLA-DR3 expression system to dissect MHC II-thyroglobulin peptide dynamism: A genetic, biochemical, and reverse immunological perspective. J Biol Chem 2009; 284: 34231-34243. PMCID: PMC2797193.

 

8. Villano MJ, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y. Autoimmune thyroiditis and diabetes: Dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009; 94: 1458-1466. PMCID: PMC2682473. 9. Menconi F, Osman R, Monti MC, Greenberg DA, Concepcion ES, Tomer Y. Shared molecular amino acid signature in the HLA-DR peptide binding pocket predisposes to both autoimmune diabetes and thyroiditis. Proc Natl Acad Sci USA 2010; 107: 16899-16903. PMCID: PMC2947869. 10. Akeno N, Smith EP, Stefan M, Huber AK, Zhang W, Keddache M, Tomer Y. Interferon-alpha mediates the development of autoimmunity both by direct tissue toxicity and through immune-cell recruitment mechanisms. J Immunol 2011; 186: 4693-4706. PMCID: PMC3106338. 11. Hasham A, Tomer Y. The recent rise in the frequency of type 1 diabetes: who pulled the trigger? J Autoimmun 2011; 1-2. PMCID: PMC3529131. 12. Stefan M, Jacobson EM, Huber AK, Greenberg DA, Li CW, Skrabanek L, Concepcion E, Fadlalla M, Ho K, Tomer Y. Novel variant of thyroglobulin promoter triggers thyroid autoimmunity through an epigenetic interferon alphamodulated mechanism. J Biol Chem 2011; 286: 31168-31179. PMCID: PMC3173071. 13. Huber AK, Finkelman FD, Li CW, Concepcion E, Smith E, Jacobson E, Latif R, Keddache M, Zhang W, Tomer Y. Genetically driven target tissue overexpression of CD40: A novel mechanism in autoimmune disease. J Immunol 2012; 189: 3043-3053. PMCID: PMC3436983. 14. Tomer Y, Hasham A, Davies TF, Stefan M, Concepcion E, Keddache M, Greenberg DA. Fine mapping of loci linked to autoimmune thyroid disease identifies novel susceptibility   206

genes. J Clin Endocrinol Metab 2013; 98: E144-152, Epub. PMCID: PMC3537111. 15. Stefan M. Zhang W, Concepcion E, Zhengzi Y, Tomer Y. DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmu, ePub.

BIOGRAPHICAL SKETCH NAME Xiong, Huabao EDUCATION/TRAINING INSTITUTION AND LOCATION Southeast University School of Medicine, Nanjing, China Niigata University School of Medicine, Niigata, Japan A. Personal Statement The studies we propose here are a direct extension of our recent findings. We have demonstrated that IRF8 deficiency in conventional as well as T cell-specific IRF8 knockout mice dominantly leads to efficient Th17 cell differentiation without affecting either the Th1 or Th2 cell lineages. Indeed, IRF8 deficiency results in more severe intestinal inflammation with an enhanced Th17 phenotype in an experimental model of colitis. Interestingly, the enhancement of IL-17+TNFa+ Th17 cell subpopulation was significantly increased in IRF8 deficient mice and correlated with the exacerbation of colitis in RAG-/- mice reconstituted with IRF8-/- T cells. These findings define a novel Th17 cell subpopulation and highlight the importance of IL17+TNFa+ Th17 cells in the development of colitis. My laboratory has extensive expertise in infection models, transcriptional regulation, cytokine biology, macrophage and T cell biology, as well as different murine colitis models. Thus I have the knowledge and experience required to administer this grant. B. Positions and Honors Positions and Employment 1989 – 1992 Assistant Professor, National Center for Sexually Transmitted Diseases, Chinese Academy of Medical Sciences, China 207

POSITION TITLE Associate Professor DEGREE M.D.

YEAR(s) 1984

FIELD OF STUDY Medicine

Ph.D.

1997

Immunology

1997 – 2000 Assistant Professor, Department of Molecular Neurobiology Brain Research Institute, Niigata University, Japan 2000 – 2001 Postdoctoral Fellow, Immunobiology Center Mount Sinai School of Medicine 2001 – 2006 Research Assistant Professor, Immunobiology Center Mount Sinai School of Medicine 2006 – 2013 Assistant Professor, Immunology Institute, Department of Medicine Mount Sinai School of Medicine 2013 – Present Associate Professor, Immunology Institute, Department of Medicine Ichan School of Medicine at Mount Sinai Honors and Awards Fellowship from Japanese Society for the Promotion of Sciences, 1997-2000, Niigata University Scholarship from Ministry of Education of Japan, 1992-1997, Niigata University C. Selected peer-reviewed publications (75 publications) (in chronological order) *indicates that the author is corresponding author.

1. *Xiong, H., Zhu. C., Chen, F., Mayer, L. Unkeless, J., Plevy, S. Complex formation of Interferon (IFN) consensus sequencebinding protein with IRF-1 is essential for murine macrophage IFN-g-induced iNOS gene expression. Journal of Biological Chemistry 278: 2271-2277, 2003. 2. Xiong, H., Zhu, C., He, K., Babyastski, M., Plevy, S. Inhibition of Interleukin-12 Transcription in Murine Macrophages and Dendritic Cells. Journal of Biological Chemistry. 2004, 279: 10776-10783. 3. Liu, S., Xiao, G., Chen, Y., He, Y., Nui, J., Escalante, C., Xiong, H., Farmar, J., Debnath, A., Tien, P., Jiang, S. Interaction between the Heppad Repeat 1 and 2 regions in spike protein of SARS-associated Coronavirus (SARS-CoV): Implication for virus fusogenic mechanism and identification of fusion inhibitors. Lancet. 2004, 363: 938-947. 4. Xiong, H., Li, H. Zhao, J., Chen, Y., Unkeless J. Interaction of TRAF6 with MAST205 regulates NF-kB activation. Journal of Biological Chemistry. 2004, 279: 43675-43678. 5. Xiong, H*., Li, H., Kong, H., Chen, Y., Zhao, J., Xiong, S., Huang, B., Gu., H., Mayer, L., Ozato, K., Unkeless, J. Ubiquitin-dependent degradation of IRF-8 mediated by Cbl down-regulates IL-12 expression. Journal of Biological Chemistry. 2005, 280:23531-23539. 6. Huang, B., Zhao, J., Li, H., He, K., Chen, Y., SH, Chen, Mayer, L., Unkeless, J., Xiong, H*. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Research (priority report). 2005, 65:5009-5014. 7. Zhu, C., Anderson, A., Schubart, A., Xiong, H., Imitola, J., Khoury S., Zheng, X., Strom, T., Kuchroo., V. Galectin 9, the ligand for Tim-3 regulates IFN-g production by inducing cell death in effector Th1 cells. Nature Immunology. 2005. 6:1245-1252.

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8. Zhao, J., Kong, HJ., Li, H., Huang, B., Yang, M., Zhu, C., Bugonovic, M., mayer, L., Ozato, K., Unkeless, J., Xiong, H*. IRF-8/ICSBP is involved in TLR signaling and contributes to the cross talk between TLR and IFN-g signaling pathways. Journal of Biological Chemistry. 2006, 281:10073-10080. 9. Huang, B., Zhao, J., Shen, S., Li, H., He, K., Shen, G., Mayer, L., Unkeless, J., Li, D., Yuan, Y., Zhang, G., Xiong, H*., Feng, Z. Listeria monocytogenes promotes growth via tumor cell TLR2 signaling. Cancer Research. 2007. 67: 4346-4352. The final two authors are equal corresponding authors. 10. Li, H., Chehade, M., Liu, W., Xiong, H., Mayer, L., Berin, C. Allergen-IgE complexes trigger CD23-dependent CCL20 release from human intestinal epithelial cells. Gastroenterology. 2007, 133:1905-1915 11. Huang, B., Zhao, J., Unkeless, J., Feng, Z., Xiong, H.* TLR signaling by tumor and immune cells: a double edged sword. Oncogene. 2008, 27:218-224. 12. Yang, J., Yang, M., Htut, T., Ouyang, X., Hanido, A., Li, X., Jiang, H., Zhang, S., Li, H., Ting, A., Mayer, L., Unkeless, J. Labadia, M., Hodge, M.m Li, J., Xiong, H.* Ebsterin-Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORgt. European Journal of Immunology. Frontline. 2008, 38:1204-1214. 13. He, K., Deora, A., Xiong, H., Ling, Q., Weksler, B., Niesvizky, R., Hajjar, H. Endothleial cell annexin A2 regulates Polyubiquitination and degradation of its binding partner S100A10/p11. Journal of Biological Chmeistry. 2008, 1919219200. 14. Gu, Y., Yang, J., Ouyang, X., Liu, W., Li, H., Yang, J., Bromberg, J., Chen, S., Mayer, L., Unkeless, J., Xiong, H.* Interleukin 10 suppresses Th17 cytokines secrted by macrophages and T cells. European Journal of Immunology. Frontline. 2008, 38:1807-1813.

15. Huang, B., Lei, Z., Zhang, G., Li, D., Song, C., Li, B., Liu, Y., Yuan, Y., Unkeless, J., Xiong, H., Feng, Z. SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood. 2008, 112:1269-1279. 16. Fingerle-Rowson, G., Kaleswarapu, D., Schlander, C., Kabgani, N., brocks, T., reinart, N., Busch, R., Lue, H., liu, A., Xiong, H., Chen, Y., Nemajerova, A., hallek, M., Bernhagen, J., leng, L., Bucala, R. A tautomerse-null macrophage migration-inhibitory factor (MIF) gene knock-in mouse model reveals that protein interactions mediates MIFdependent growth regulation. Molecular and Cellular Biology. 2009, 29:1922-1932. 17. Liu, W., Ouyang, X., Yang, J., Liu, J., Li, Q., Gu, Y., Fukata, M., Lin, T., He, JC., Abreu, M., Unkeless, JC., Mayer, L., Xiong, H.* AP-1 regulates expression of IL-23 p19. Journal of Biological Chemistry. 2009, 284: 24006-16. 18. He, B., Santamaria, R., Xu, W., Cols, K., Chen, K., Puga, I., Shan, M., Xiong, H., Bussel, JB., Chiu, A., Puel, A., Reichenbach, J., marodi, L., Doffinger R., Vasconcelos, J., Issekutz, A., Krause J., Davies, G., Li, X., grimbacher, B., Plebani, A., Meffre, E., Picard, C., Cunningham-Rundles, C., Casanova, JL. The trnasmemebrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nature Immunology, 2010, 11: 836-845. 19. Ouyang, X., Yang, Z., Zhang, R., Arnaboldi, P., Lu, G., Li, Q., Wang, W., Zhang, B., Cui, M., Zhang, H., Liang-chen, J., Qin, L., Zheng, F., Huang, B., Xiong, H.* Potentiation of Th17 cytokines in aging process contributes to the development of colitis. Cellular Immunology. 2011, 266:208-217. 20. Ouyang, X., Zhang, R., Yang, J., Li, Q., Qin, L., liu, J., Ning, H., Shin, M., Gupta, M., Qi, C., He, C., Lira, S., Morse, H., Ozato,

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K., Mayer, L., Xiong, H*. Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation. Nature Communications. 2011, 2:314 21. Jin, Y., Ratnam, K., Chuang, P., Fan, Y., Zhong, Y., Dai, Y., Mazloom, A., Chen, E., D’Agati, V., Xiong, H., Ross, M., Chen, N., Ma’ayan, A., He, J. System approach identifies HIPK2 as a critical regulator of kidney fibrosis. Nature Medicine. 2012, 18:580-588. 22. Greter, M., Helft, J., Bogunovic, M., Gautier, E., Leboeuf, M., Chow, A., Miller, J., hashimoto, D., Beltran, A., Lu, G., Aloman, C., Pollard, J., Xiong, H., Randolph, G., Merad, M. GM-CSF is a stedy state cytokine thsat control nonlymphoyd tissue resident DC homeostasis but is dispensible for the differentiation of inflammatory DC. Immunity. 2012, 36:1031-1046. 23. Yang, J., Zhang, R., lu, G., Shen, Y., Peng, L., Zhu, C., Cui, M., Wang, W., Arnaboldi, P., Tang, M., Gupta, M., Qi, C., Jararaman, P., Zhu, H., Jiang, B., Chen, S., He, J., Ting, A., Zhou, M., Kuchroo, V., Morse, H., Ozato, K., Sikora, A., Xiong, H*. T cell-derived inducible nitric oxide synthase switches off Th17 cell differentiation. Journal of Experimental Medicine. 2013, 210:1447-1462. 24. Zhang, R., li, Q., Chuang, P., Lu, G., Liu, R., Yang, J., Peng, L., Dai, Y., Zhang, Z., Qi, C., He, J., Xiong, H*. Regulation of pathogenic Th17 cell differentiation by interleukin 10 in the development of glomerulonephritis. The American Journal of Pathology. 2013, 183: 402-412. 25. Shan, M., Gentile, M., Yeiser, J., Walland, A., Bornstein, V., Chen, K., He, B., Cassis, L., Bigas, A., Cols, M., Comerma, L., Huang, B., Blander, J., Xiong, H., Mayer, L., Berin, C., Augenlicht, L., Velcich, A., Cerutti, A. Mucus enhances gut homeostasis and oral tolerance by delivering imunoregulatory signals. Science. 2013, 342: 447-453.

BIOGRAPHICAL SKETCH NAME Yeretssian, Garabet EDUCATION/TRAINING INSTITUTION AND LOCATION

DEGREE

MM/YY

Lebanese University, Beirut

M.S.

03/01

University of Bourgogne, Dijon

M.S.

09/02

University of Nantes McGill University, Montreal

Ph.D. Postdoctoral

01/06 02/11

A. Personal Statement I have been steadily pursuing a research program that aims to study innate immunity and cell death pathways towards the discovery of novel biological therapeutics for inflammatorymediated immune disorders. The primary focus of my research program is to elucidate the molecular mechanisms and roles of cytosolic pattern recognition receptors of the Nod-like receptor (NLR) family in host defense, chronic inflammation and cancer. Several established approaches, ranging from genetically modified mouse models to biochemistry and cellular immunology methods, are used in my laboratory to gain insight into the mechanisms that govern host-microbiota and hostpathogen interactions in health and disease. As a postdoctoral fellow at McGill University, I have particularly investigated the functions of various apoptosis effectors in infection, inflammatory bowel diseases and colorectal cancer. My broad experience allows me to tackle questions about the molecular mechanisms that regulate inflammatory responses and apoptosis in the cell. In addition, I have a demonstrated track record of collaborative, successful, highly productive, and focused research projects of the hand. My previous experiences 210

POSITION TITLE Assistant Professor FIELD OF STUDY Animal Biology (Microbiology and Immunology) Biochemistry, Cell and Molecular Biology Cellular and Molecular Biology Immunology and Microbiology

allow me to construct a realistic research plan, timeline and budget. B. Positions and Honors Positions and Employment 2006 Principal Investigator (R&D), ProtNeteomix SAS, Nantes, France 2006-2010 Research Postdoctoral Fellow, Department of Medicine, McGill University, Montreal 2010-2011 Associate Research Scientist, Department of Medicine, McGill University, Montreal 2011- Assistant Professor, Immunology Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York 2012- Assistant Professor, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York Honors and Awards 2000 Best Abstract Award, UNESCO Medica 2000, Beirut, Lebanon 2001-2002 Calouste Gulbenkian Foundation Scholar 2001 Master of Science, with distinction 2002 Dean’s Honor List, University of Bourgogne, Dijon, France

2002-2003 Armenian General Benevolent Union (AGBU) Scholar 2003-2006 Centre National de la Recherche Scientifique (CNRS) doctoral fellow 2005 Travel Award from Human Proteome Organization (HUPO), Munich, Germany 2005-2006 Association de la Recherche pour le Cancer (ARC) doctoral fellow 2006 Ph.D. with Honors, University of Nantes, France 2008-2010 McGill University Health Center (MUHC) Postdoctoral Fellow (ranked 1st for two consecutive years) 2011 Best Presentation Award, PDGI 2011, Orford, Canada 2013 Ellison Medical Foundation – New Scholar; Nominated through Mount Sinai Service 2012- Co-director of the Immunology Institute Journal Club 2012- Member of the Advisory Postdoctoral Committee; Mount Sinai Ad-hoc reviewer for projects Broad Foundation; Canadian Institute of Health Research; Israel Science Foundation; Association de la Recherche sur le Cancer Ad-hoc reviewer for scientific journals Bentham Science Publisher, Cancer research, Frontiers in Immunology, Immunity, Inflammatory bowel disease, Journal of Crohn’s Colitis, Mucosal Immunology, Nature, Nature Immunology, Oncogene, Plos One C. Publications 1. Yeretssian G., Lecocq M., Lebon G., Hurst H.C., Sakanyan V. Competition on nitrocellulose immobilized antibody arrays: From bacterial protein binding assay to protein profiling in breast cancer cells. Molecular and Cellular Proteomics 2005, 4(5), 605-617. PMID: 15691851. PMCID Journal – in Process.

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2. Shao W., Yeretssian G., Doiron K., Hussain SN., Saleh M. The caspase-1 digestome identifies the glycolysis pathway as a caspase-1 target during Salmonella infection and in septic shock. Journal of Biological Chemistry 2007, 282(50): 36321-9. PMID: 17959595. PMCID Journal – in Process. 3. Gaudin JC., Rabesona H., Choiset Y., Yeretssian G., Chobert JM., Sakanyan V., Haertle T. Assessment of the IgE-mediated immune response to milk-specific proteins in allergic patients using microarrays. Clinical and Experimental Allergy 2008, 38(4): 686-93. PMID: 18307527. PMCID Journal – in Process. 4. LeBlanc PM., Yeretssian G., Rutherford N., Doiron K., Nadiri A., Zhu L., Green DR., Gruenheid S., Saleh M. Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host and Microbe 2008, 13; 3(3): 146-57. PMID: 18329614. PMCID Journal – in Process. 5. Yeretssian G., Labbe K., Saleh M. Molecular regulation of inflammation and cell death. Cytokine 2008, 43(3):380-90. PMID: 18703350. PMCID Journal – in Process. 6. *McIntire CR., *Yeretssian G., Saleh M. Inflammasomes in infection and inflammation. Apoptosis 2009, 14(4): 522-35. *(Shared first authorship). PMID: 19156527. PMCID Journal – in Process. 7. Yeretssian G., Doiron K., Shao W., Leavitt BR., Hayden MR., Nicholson DW., Saleh M. Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection. Proceedings of the National Academy of Science 2009, 106(22): 9016-20. PMCID: PMC2690057. 8. *Yeretssian G., *Dupaul-Chicoine J., Doiron K., Bergstrom KS., McIntire CR., LeBlanc PM., Meunier C., Turbide C., Gros P., Beauchemin N., Vallance BA., Saleh M. Control of

9.

10.

11.

12. 13.

14.

intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 2010, 32(3):367-78. *(Shared first authorship and Cover story). PMID: 20226691. PMCID Journal – in Process. Labbe K., *Miu J., *Yeretssian G., Serghides L., Tam M., Finney CA., Erdman LK., Goulet ML., Kain KC., Stevenson MM., Saleh M. Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kB signaling. Journal of Immunology 2010, 185(9): 5495502. *(Shared second authorship). PMID: 20876354. PMCID Journal – in Process. Yeretssian G., Correa RC., Doiron K., Fitzgerald P., Dillon CP., Green DR., Reed JC., Saleh M. Non-apoptotic role of BID in inflammation and innate immunity. Nature 2011, 474(7349): 96-9. PMID: 21552281. PMCID Journal – in Process. Yeretssian G. Effector functions of NLRs in the intestine: innate sensing, cell death, and disease. Immunological Research 2012; 54 (1-3):25-36. PMID: 22454103. PMCID Journal – in Process. Muniz LR., Knosp C., Yeretssian G. Intestinal antimicrobial peptides during homeostasis, infection and disease. Frontiers in Immunology 2012; 3:310. PMCID: PMC3466489. Meunier C., Van Der Kraak L., Turbide C., Groulx N., Labouba I., Cingolani P., Blanchette M., Yeretssian G., Mes-Masson AM., Saleh M., Beauchemin N., Gros P. Positional mapping and candidate gene analysis of the mouse ccs3 locus that regulates differential susceptibility to carcinogen-induced colorectal cancer. PLOS One 2013; 8: e58733. PMCID: PMC3597735. Roda G., Jianyu X., Park MS., DeMarte L., Hovhannisyan Z., Ronald C., Stanners CP., Yeretssian G., Mayer L. Characterizing CEACAM5 interaction with CD8a and CD1d in intestinal homeostasis. Mucosal Immunology 2013 Oct 9.

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doi: 10.1038/mi.2013.80. (Co-supervised the study in lieu of Dr. Mayer). PMID: 24104458. PMCID Journal – in Process. 15. Mathern DR., Laitman LE., Hovhannisyan Z., Dunkin D., Farsio S., Malik TJ., Roda G., Chitre A., Iuga AC., Yeretssian G., Berin MC., Dahan S. Mouse and human Notch-1 regulate mucosal immune responses. Mucosal Immunology. 2014 Jan 15. PMID: 24424521. PMCID Journal – in Process.

BIOGRAPHICAL SKETCH NAME Zhou, Lan EDUCATION/TRAINING INSTITUTION AND LOCATION Shanghai Medical University, China Shanghai Huashan Hospital, China University of Cincinnati, OH University of Cincinnati, OH Wayne State University, MI Johns Hopkins University, MD A. Personal Statement I am a neurologist subspecialized in neuromuscular diseases. I am also a research scientist with an active basic research program. Our lab is interested in determining the recruitment and functions of monocyte subsets with respect to muscle inflammation, fibrosis, and regeneration associated with acute skeletal muscle injury repair and chronic muscular dystrophy. We use chemical-induced acute skeletal muscle injury model, the Duchenne muscular dystrophy (DMD) mouse model, mdx mice, and various chemokine receptor knockout mouse models for our study which is supported by NIH. Our previous studies showed that modulating muscle inflammatory responses and targeting muscle fibrosis represent a viable approach for treating DMD, which is a most common, lethal, and currently untreatable disease. The ultimate goal of our research is to develop novel therapies for DMD by modulating the recruitment and functions of monocytes/macrophages. B. Positions and Honors Positions and Employment 2003-2004 Clinical Associate, Department of Neurology, Cleveland Clinic 213

POSITION TITLE Associate professor DEGREE M.D. resident Ph.D. Post-doc resident Fellow

MM/YY 1989 1989-1991 1995 1995-1997 1998-2002 2002-2003

FIELD OF STUDY Neurology Molecular Biology Molecular Biology Neurology Neuromuscular

2004-2007 Associate Staff, Department of Neurology, Cleveland Clinic 2007-2011 Staff, Departments of Neurology and Neurosciences, Neurological Institute and Lerner Research Institute, Cleveland Clinic 2012-date Associate professor, Department of Neurology, Mount Sinai School of Medicine Other Experience and Professional Memberships 2001Member, American Academy of Neurology 2002- Member, American Association of Neuromuscular and Electrodiagnostic Medicine 2007- Member, American Muscle Study Group 2009- Member, Peripheral Nerve Society 2010- Study section, NIH Wellstone Muscular Dystrophy Cooperative Research Centers (MDCRC) U54 Honors 1994 Albert J. Ryan Fellowship, The Albert J. Ryan Foundation 1995 Honorable Mentioning, Fifteenth Annual Graduate Student Research Forum, University of Cincinnati College of Medicine

2001 Chief Resident, Wayne State University Department of Neurology 2002 Resident Scholarship, American Academy of Neurology 2007 Travel Award, American Society of Clinical Investigation/American Association of Physicians C. Peer-reviewed Publications 1. Zhou L, Dey CR, Wert SE, DuVall MD, Frizzell RA, and Whitsett, JA. (1994) Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science. 266:1705-1708. 2. Simonet WS, DeRose ML, Bucay N, Nguyen HQ, Wert SE, Zhou L, Ulich TR, Thomason A, Danilenko DM, and Whitsett JA. (1995) Pulmonary malformation in transgenic mice expressing human keratinocyte growth factor in the lung. Proc Natl Acad Sci USA. 92:1246-1255. 3. Zhou L, Dey CR, Wert, SE, and Whitsett JA. (1996) Arrested lung morphogenesis in transgenic mice bearing an SP-CTGF-B1 chimeric gene. Dev Biol. 175:227-238. 4. Zhou L, Lim L, Costa RH, and Whitsett JA. (1996) Thyroid transcription factor-1 hepatocyte nuclear factor-3B, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung. J Histochem Cytochem. 44:11831193. 5. Zhou L, Graeff RW, McCray PB Jr, Simonet WS, and Whitsett JA. (1996) Keratinocyte growth factor stimulates CFTRindependent fluid secretion in the fetal lung in vitro. Am J Physiol. 271:L987-994. 6. Whitsett JA. and Zhou L. (1996) Use of transgenic mice to study autocrine-paracrine signaling in lung morphogenesis and differentiation. Clin Perinatol. 23: 753-769. 7. Zhou L, Dey CR, Wert SE, Tan C, Costa RH, and Whitsett JA. (1997) Hepatocyte nuclear factor-3B limits cellular diversity

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in the developing respiratory epithelium and alters lung morphogenesis in vivo. Dev Dynamics. 210:305-311 Zhou L, Zabad R, and Lewis RA. (2002) Ethylene glycol intoxication: Electrophysiological studies suggest a polyradiculopathy. Neurology. 59 (11): 1809-1810. Zhou L, Chillag K, and Nigro MA. (2003) Hyperekplexia: a treatable neurogenetic disease. Brain & Dev. 24 (7): 669-674. Zhou L. and Griffin JW. (2003) Demyelinating neuropathies. Curr Opin Neurol. 16 (3): 307-313. Zhou L, McConville J, Chaudhry V, Adams RN, Skolasky RL, Vincent A, and Drachman DB. (2004) Clinical comparison of MuSK antibody positive and negative myasthenic patients. Muscle Nerve. 30(1): 55-60. Zhou L, Yousem DM, and Chaudhry V. (2004) Role of magnetic resonance neurography in brachial plexus lesions. Muscle Nerve. 30(3): 305-309. Zhou L and Hoke A. (2004) A novel insertional mutation in the Connexin 32 gene causes CMTX with unusual elecetrophysiological findings. J Peripher Nerv Syst. 9: 194195. Bolanos-Meade J, Zhou L, Hoke A, Corse A, Vogelsang G, Wagner KR. (2005) Hydroxychloroquine causes severe vacuolar myopathy in a patient with chronic graft-versushost disease. Am J Hematol. 78 (4): 306-309. Zhou L, Porter JD, Cheng G, Gong B, Hatala DA, Merriam AP, Zhou X, Rafael-Fortney JA, Kaminski HJ. (2006) Temporal and spatial mRNA expression patterns of TGF-b1, 2, 3 and TbRI, II, III in skeletal muscles of mdx mice. Neuromuscul Disord. 16(1): 32-38. Zhou L, Kitch D, Evans SR, Raman S, Hauer P, Ebenezer G, Gerschenson M, Marriana CM, Valcour V, Diaz-Arrastia R, Goodkin K, Millar L, Shriver S, Asmuth DM, Clifford DB, Simpson DM, McArthur JC. (2007) Correlates of epidermal

nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology. 68(24):2113-2119. 17. Chemali K and Zhou L. (2007) Small fiber degeneration in post-stroke complex regional pain syndrome. Neurology. 69(3):316-7. 18. Zhou L, Rafael-Fortney JA, Huang P, Zhao SX, Cheng G, Zhou X, Kaminski HJ, Liu L, and Ransohoff RM. (2008) Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice. J. Neurol. Sci. 264(1-2):106-111. 19. Shook SJ, Mamsa H, Jen JC, Baloh RW, Zhou L. (2008) A novel mutation in KCNA1 causes episodic ataxia with dyspnea. Muscle Nerve. 37(3):399-402. 20. Cheng G, Kaminski HJ, Gong B, Zhou L, Hatala D, Howell SJ, Zhou X, Mustari MJ. (2008) Molecular visual deprivation in Macaque monkeys: A profile in the gene expression of lateral geniculate nucleus by laser capture microdissection. Mol Vis. 4 (14):1401-13. 21. Zhou L and Pioro EP. (2009) Familial ALS with SOD1 mutation misdiagnosed with polyradiculopathy and myopathy. Amyotroph Lateral Scler. 2009;10(5-6):476-478. 22. Tavee J and Zhou L. (2009) Small fiber neuropathy: A burning problem. Cleve Clin J Med. 76(5):297-305 23. Huang P, Zhao XS, Fields M, Ransohoff RM, Zhou L. (2009) Imatinib attenuates skeletal muscle dystrophy in mdx mice. FASEB J. 23(8):2539-48. 24. Zhou L and Lu H. (2010) Targeting fibrosis in Duchenne muscular dystrophy. J Neuropathol Exp Neurol. 69(8):771-6. 25. Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver DA. (2011) Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med. 105 (1):101-5.

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26. Lu H, Huang D, Saederup N, Charo IF, Ransohoff RM, and Zhou L (2011). 2. Macrophages recruited via CCR2 signaling produce insulinlike growth factor-1 to support acute skeletal muscle injury repair. FASEB J. 25(1):358-69. 27. Huang P, Cheng G, Lu H, Aronica M, Ransohoff RM, Zhou L. (2011). Impaired respiratory function in mdx and mdx/utrn+/- mice. Muscle Nerve. 43(2):263-7. 28. Zhou L, Li J, Ontaneda D, and Sperling J (2011) Metabolic syndrome in small fiber sensory neuropathy. J Clin Neuromuscul Dis. 12(4):235-243. 29. Lu H, Huang D, Ransohoff RM, and Zhou L (2011). Acute skeketal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair. FASEB J. 25(10):3344-3355. 30. Yao Q, Zhou L, Tomecki KJ. (2011) Coexistent tumor necrosis factor receptor-associated periodic fever syndrome and Ehlers-Danlos syndrome. Rheumatol Int. 32(7):2223-5. 31. Yao Q, Zhou L, Cusumano P, Bose N, Piliang M, Jayakar B, Su LC, Shen B. (2011) A new category of autoinflammatory disease associated with NOD2 gene mutations. Arthritis Res Ther. 13(5):R148. 32. Beastrom N, Lu H, Macke A, Canan BD, Johnson EK, Penton CM, Kaspar BK, Rodino-Klapac LR, Zhou L, Janssen PM, Montanaro F. (2011) Mdx(5cv) Mice Manifest More Severe Muscle Dysfunction and Diaphragm Force Deficits than Do Mdx Mice. Am J Pathol. 179(5):2464-74 33. Khan S and Zhou L (2012) Characterization of non-lengthdependent small fiber sensory neuropathy. Muscle Nerve. 45(1):86-91 34. Cheng J, Daftari A, and Zhou L (2012) Sympathetic blocks provided sustained pain relief in a patient with refractory

painful diabetic neuropathy. Case Reports in Anesthesiology. Epub 2012. 35. Ghosh P and Zhou L (2012) Diagnostic utility of the Athena limb-girdle muscular dystrophy gene test panel. J Clin Neuromuscul Dis. 14(2):86-7 36. Yao Q, Su LC, Tomecki KJ, Zhou L, Jayakar B, and Shen B (2012) Dermatitis as a Characteristic Manifestation of a New Category of Autoinflammatory Disease Associated with NOD2 Mutations. J Am Acad Dermatol. 68(4):624-31 37. Armour R and Zhou L (2013) Outcome of statin myopathy after stain withdrawal. J Clin Neuromuscul Dis. 14(3):103-9.

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BIOGRAPHICAL SKETCH NAME Zier, Karen

POSITION TITLE Professor

EDUCATION/TRAINING INSTITUTION AND LOCATION Hofstra University SUNY of NY at Buffalo/University of Wisconsin

DEGREE B.A. Ph.D.

Professional Experience 1972-75 Pre-doctoral Trainee, Immunobiology Research Center and Department of Genetics, University of Wisconsin. 1974-77 Post-doctoral Fellow, Department of Medicine, University of Innsbruck, Austria 1977-80 Instructor, National Tissue Typing Laboratory and WHO Collaborating Laboratory, University of Munich, Germany. 1980-86 Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA. 1986-88 Associate Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA. 1988-96 Associate Professor of Medicine and Microbiology, Mount Sinai School of Medicine, New York, NY. 1996- present Professor of Medicine, Mount Sinai School of Medicine, New York, NY. 1997- present Professor, Immunology Institute, Mount Sinai School of Medicine 1998- present Professor of Microbiology, Mount Sinai School of Medicine Mount Sinai School of Medicine 1999- present Professor, Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine 1999 -present Associate Dean for Medical Student Research Other Professional Activities: 217

YEAR(s) 1968 1975

FIELD OF STUDY Biology Microbiology/Immunology

Breast Cancer Research Program, State of California, Tumor Immunology Study Section (1995). Department of Defense Breast Cancer Research Program Immunological Sciences Study Section (1995) Breast Cancer Research Program, State of California, Tumor Immunology Study Section (1995) Department of Defense Breast Cancer Research Program Immunological Sciences Study Section (1996) Member, NIH, Immunology, Virology, and Pathology Study Section (1996Ad Hoc Member, NIH Program Project Study Section (1997). Breast Cancer Research Program, State of California, Innovative Treatments Study Section (1997). Department of Defense Breast Cancer Research Program Immunological Sciences Study Section (1997) Ad Hoc Member, NIH (NCI) Program Project Study Section (1998). 1998- present Director, Office of Research Opportunities, Department of Defense Breast Cancer Research Program Immunological Sciences Study Section (1999) Department of Defense Breast Cancer Research Program Immunological Sciences Study Section (2000, invited) Department of Defense Breast Cancer Research Program Immunological Sciences Study Section (2002)

NIH Study Section, Cancer Immunopathology and Health Research Science Board, New York State (Gubernatorial Appointment) 2009 Bibliography: (Selected publications) 1. Gansbacher, B., Zier. K., Daniels B. Cronin K, Bannerji, R. and Gilboa, E. IL-2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J. Exp.Med.,172:1217-1224, 1990. 2. Gansbacher, B., Bannerji, R., Daniels, B., Zier K., Cronin, K., and Gilboa, E. Retroviral vector mediated IFN-gamma gene transfer into tumor cells generates potent and long lasting anti-tumor immunity. Cancer Res., 50:7820-7825, 1990. 3. Gansbacher, B., Zier K., Houghton, A., Gilboa, E. and Golde, D. Gene transfer induced constitutive expression of IL2 or IFN-gamma by irradiated human melanoma cells. Blood 80:2817-2825, 1992. 4. Salvadori S., Rosenthal F, Cronin K, Gansbacher B. and Zier K.S. Tumor bearing animals contain suppressed anti-tumor effectors whose function can be unmasked by IL-2. J. Immunother., 14:216, 1993. 5. Zier K.S., Salvadori, S., Cronin, K., and Gansbacher, B. Vaccination with IL-2-secreting tumor cells stimulates the generation of IL-2 responsive T cells and prevents the development of subsequent unresponsiveness. Cancer Gene Ther., 1:43, 1994. 6. Salvadori, S., Gansbacher, B., Pizzimenti, A., and Zier, K.S. T cells from mice vaccinated with IL-2 secreting tumor cells are protected from the onset of signal transduction abnormalities seen in T cells of mice bearing parental tumors. J. Immunol., 153:5176-5182, 1994. 7. Salvadori, S., Gansbacher, B., and Zier K.S. Functional differences are associated with abnormal signal transduction   218

Immunotherapy (2006, invited 2007)

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in T cells of mice inoculated with parental but not IL-2 secreting tumor cells. Cancer Gene Ther., 1:165-170, 1994. Salvadori, S., Gansbacher, B., Wernick, I., Tirelli, S. and Zier, K. B7-1 transfected tumor cells induce a response in syngeneic hosts in vivo, but fail to stimulate naive allogeneic cells in vitro. Hum. Gene Ther., 6:1299-1306, 1995. Zier K.S. and Gansbacher, B. The impact of gene therapy on T cell function in cancer. Hum. Gene Ther., 6:1259-1264, 1995. Zier, K., Gansbacher, B., and Salvadori, S. Preventing abnormalities in signal transduction of T cells in cancer: the promise of cytokine gene therapy. Immunol. Today, 17:39-45, 1996.22. Zier, K.S. and Gansbacher, B.G. IL-2 gene therapy of solid tumors: An approach for the prevention of signal transduction defects in T cells. J. Mol. Med., 74:127, 199 Salvadori, S. and Zier, K. The molecular basis of T cell dysfunction in cancer is influenced by the paracrine secretion of tumor-derived IL-2. J. Immunol., 156:2927, 1996. Zier, K.S. and Gansbacher, B.G. Tumor cell vaccines that secrete IL-2 and IFNg are recognized by T cells while selectively resisting destruction by NK cells. Eur. J. Cancer, 32A: 1408, 1996. Salvadori, S., Moran, T.P., and Zier, K. Antigen presentation by B7- non-professional APC does not prevent responses to solid tumor cells. Cellular Immunol., 183:52, 1998. Salvadori, S., Martinelli, G., and Zier, K.S. Tumor resection reverses signal transduction defects and unmasks T cell mediated protective immunity. J. Immunol. 164:2214, 2000. Zier, K., Johnson, K., Maddux, J-M., Sung, M., Mandeli, J., and Schwartz, M. Antigen Specific Secretion of IFNγ Against

 

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Tumor Peptides Prepared from Fresh Tumor Tissue in Colon Cancer Patients. J. Immunol. Meths, 241:61, 2000. Zier, K., Maddux, J-M., Johnson, K., Sung, M., Mandeli, M., and Schwartz, M. Surrogate Markers of Anti-tumor Responses: In vitro Activation of T cells by Autologous Tumor Peptides. Clin. Cancer Res 7:818s-821s, 2001. Bartido, S. and Zier, K. T cell responses to multiple antigens presented by RNA-transfected APCs: A possible immunomonitoring tool, Cancer Immunol. Immunother., 53:100, 2004. Zier, K., Friedman, E., and Smith, L. Supportive programs increase medical students’ research interest and productivity. J. Invest. Med., 54:201-207, 2006. Cohen, B., Friedman, E., and Zier, K. Publications by Students Doing A Year of Full-Time Research: What are Realistic Expectations? Am. J. Med., 121:545-8, 2008.

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20. Zier KS, and Coplit, L. Expanding Opportunities for Scholarship in Undergraduate Medical Education: The Individual Scholarly Project and Independent Research Experience (INSPIRE). Mt. Sinai J. Med., 76:387-391, 2009. 21. Zier KS, Wyatt C, and Muller D. An Innovative Portfolio of Research Training Programs for Medical Students. Immunol. Res., 54:286, 2012. 22. Zier KS and Friedman, E. Is A Publication An Expected Outcome of Medical Student Research. Manuscript submitted. 23. Chaudhari P, Friedman E, Coplit L, Fallar R, Zier K. Academic and Social Concerns of Medical Students on a Scholarly Leave. Submitted.

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