II. Abstract: Autoimmunity is a self-destructive immune disorder and often directed towards a particular tissue or organ. Although the disease manifestations can be tissue-specific, they do not necessarily originate in that particular tissue. Furthermore, individuals with a specific autoimmune disease are at risk to develop additional autoimmunity directed towards other target tissues. What all autoimmune diseases do have in common is that they result from a breakdown in self-tolerance, with a major contribution from pathogenic self-reactive T cells. T cell tolerance towards ?self? is initially established in the thymus during the process of thymic selection. Strong self-reactive T cells are either clonally deleted or alternatively clonally deviated to become regulatory T cells that are key suppressors of auto-aggressive immune cells. Since this decisive selection process plays a fundamental role in self-tolerance, we postulate that susceptibility to autoimmunity might originate from a principal defect in the central process that governs clonal deletion versus clonal deviation. The proposal will test this hypothesis and ultimately seek to identify the primary deficiency and contributing factors that underlie susceptibility to autoimmunity. Understanding the defect(s) is this selection process will ultimately allow for early detection of individuals that are at a high risk to develop autoimmune diseases. Aside from detecting autoimmune susceptibility, this research will have vital implications for the prevention and effective treatment of autoimmune diseases. Although it is feasible to induce the production of suppressive regulatory T cells through immunization with selfantigens, it is possible that pathogenic self-reactive cells will be generated, thus exacerbating the disease. Our proposed study will explore a novel strategy to prevent and/or treat autoimmunity. Hepatic stellate cells will be used as natural, regulatory, antigen-presenting cells to assure the efficient generation of regulatory T cells that may suppress pathogenic autoimmune cells and thereby control autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
8DP1GM105384-04
Application #
8318169
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (02))
Program Officer
Marino, Pamela
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$935,055
Indirect Cost
$440,055
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Mucida, Daniel; Husain, Mohammad Mushtaq; Muroi, Sawako et al. (2013) Transcriptional reprogramming of mature CD4? helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat Immunol 14:281-9
Cheroutre, Hilde; Husain, Mohammad Mushtaq (2013) CD4 CTL: living up to the challenge. Semin Immunol 25:273-81