This proposal outlines an integrative five-year training program for the candidate, Arnold Han, M.D., Ph.D., in his development as an independent physician-scientist. Dr. Han is clinically trained as a gastroenterologist and has a Ph.D. in immunology. He is doing postdoctoral research under the mentorship of Dr. Mark Davis, Professor of Microbiology and Immunology at Stanford University and Investigator with the Howard Hughes Medical Institute. In his proposal entitled The intraepithelial T cell response in celiac disease, Dr.
Han aims to better understand celiac disease (CD), an incurable autoimmune disease that affects millions of Americans, and many more worldwide. The research further investigates the observation that intraepithelial T lymphocytes (T-IEL) in CD are deliberately recruited to the intestine in response to gluten. T-IELs are the cells held responsibl for the detrimental consequences of CD, including intestinal damage and lymphoma development. As a follow up, the proposal aims to better understand mechanisms through with T-IEL are activated and recruited to the intestine in CD. The research explores the hypothesis that gluten-specific CD4+ T cell responses enable T-IEL responses directed against antigens other than gluten. The proposed research investigates the nature and mechanisms of T-IEL responses in CD through the following aims: 1) Examine the mechanisms through which gluten enables ?? T cell activation in celiac disease through the study of ?? T cell function in peripheral blood and tissue. 2) Examine the mechanisms through which gluten enables tissue damage by CD8+ T cells in CD. 3) Analyze mechanisms through which T-IELs are activated and recruited to the intestinal epithelium through the study of antigen-specific T-IEL responses in humanized mouse models.
These aims leverage Dr. Han's clinical training in gastroenterology, his post-doctoral research training in the study of human mucosal T cells, and the expertise of the Mark Davis laboratory and collaborators. Successful completion of these aims may ultimately enable the development of novel approaches in the prevention and treatment of CD and other autoimmune diseases. Concurrently, Dr. Han will complete a structured career development-training program, overseen by mentors within the Division of Gastroenterology and Hepatology and other faculty at the Stanford University School of Medicine. This plan will include didactic, clinical, and managerial experience necessary to achieve Dr. Han's ultimate goal of becoming a successful, independent physician-scientist.

Public Health Relevance

The intestine is frequently affected by autoimmunity. Celiac disease, a lifelong incurable autoimmune disease affecting 1% of Americans, alters the quality of life of all those afflicted and in some cases may directly lead to a life-threatening lymphoma. Immune cells called T cells are critical in celiac disease. This proposal aims to understand how and why T cells respond improperly to a benign dietary protein that they should normally tolerate. These studies will provide insights into celiac disease and more broadly into other autoimmune diseases. The ultimate hope is to enable novel diagnostics and therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Saslowsky, David E
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Gee, Marvin H; Han, Arnold; Lofgren, Shane M et al. (2018) Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes. Cell 172:549-563.e16
Yan, Kelley S; Gevaert, Olivier; Zheng, Grace X Y et al. (2017) Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity. Cell Stem Cell 21:78-90.e6
Yan, Kelley S; Janda, Claudia Y; Chang, Junlei et al. (2017) Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 545:238-242
Glanville, Jacob; Huang, Huang; Nau, Allison et al. (2017) Identifying specificity groups in the T cell receptor repertoire. Nature 547:94-98
Hansmann, Leo; Han, Arnold; Penter, Livius et al. (2017) Clonal Expansion and Interrelatedness of Distinct B-Lineage Compartments in Multiple Myeloma Bone Marrow. Cancer Immunol Res 5:744-754
Wei, Yu-Ling; Han, Arnold; Glanville, Jacob et al. (2015) A Highly Focused Antigen Receptor Repertoire Characterizes ?? T Cells That are Poised to Make IL-17 Rapidly in Naive Animals. Front Immunol 6:118
Han, Arnold; Glanville, Jacob; Hansmann, Leo et al. (2014) Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nat Biotechnol 32:684-92