Autoimmune diseases like type 1 diabetes arise through a breakdown in immune tolerance. We have now come to understand that immune tolerance consists of a multi-layered network that keeps such untoward responses in check. In this program project grant, three complementary teams will be working together to further unravel how these checkpoints operate to improve our understanding of autoimmunity and ultimately improve its treatment. This program project will have three highly collaborative and interactive projects headed by Drs. Mark Anderson (Project 1), Jeff Bluestone (Project 2) and John Kappler (Project 3) along with two scientific cores (Animal core and Molecular core). The major themes of the grant are: 1. The impact of central thymic tolerance on the T effector and Treg repertoire in T1D.. 2. Insulin as a critical self-antigen specificity for both T effectors and T regulatory cells in T1D. 3. Peptide specificity of Tregulatory cells in T1D 4. Using peptide binding characteristics of islet antigens to improve bioassays and tolerance methods. The long term objectives of this work is to improve our understanding of how T cell tolerance is controlled and the further refining the specificity of the autoreactive T cell response in type 1 diabetes. The investigators will be using state of the art tools in both animal models and in human subjects with type 1 diabetes. Results of these studies will help further refine our understanding of autoimmunity and help improve methods for its treatment and diagnosis.

Public Health Relevance

This is a program project grant that is centered on improving our understanding of how self-reactive T cells develop or are kept in check in autoimmune type 1 diabetes. The results of the projects here will help improve our ability to both detect and devise logical treatment strategies for this autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI118688-05
Application #
9942357
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Rice, Jeffrey S
Project Start
2016-06-08
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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Spence, Allyson; Purtha, Whitney; Tam, Janice et al. (2018) Revealing the specificity of regulatory T cells in murine autoimmune diabetes. Proc Natl Acad Sci U S A 115:5265-5270
McKee, Amy S; Marrack, Philippa (2017) Old and new adjuvants. Curr Opin Immunol 47:44-51
Proekt, Irina; Miller, Corey N; Lionakis, Michail S et al. (2017) Insights into immune tolerance from AIRE deficiency. Curr Opin Immunol 49:71-78