Fas (Apo-1, CD95), has been implicated in the regulation of normal and auto-specific immune responses. The role of Fas in autoimmunity is dual: it is involved in the limitation of T cell proliferation in the course of an immune response and it participates in the death of cells targeted by T cells in organ-specific autoimmune responses. Studying mice with conditional deletion of Fas from several cell types we found that mice lacking Fas from antigen presenting cells (ARC) developed systemic autoimmunity. We formulated a hypothesis that a loss of Fas receptor by APC leads to their prolonged survival, extendedpresentation of antigens to T cells, and, thus, contributes to autoimmunity observed in Fas-deficient animals and humans. We are also pursuing a hypothesis that Fas expression by target cells (insulin-producing (I cells) is critical for spontaneous development of an organ-specific autoimmune disease (type 1 diabetes). Using several already developed animal models, we will pursue the following Specific Aims:
Specific Aim 1. Determine the contribution of Fas expression by antigen-presenting T cells to normal and auto-specific immune responses. a. We will study the dynamics of Fas-sensitivity of APC and its role in the immune responses. We will also test a hypothesis that Fas-mediated elimination of APC can influence the development of chronic infections. b. We will determine how Fas-mediated death of antigen-presenting cells regulates the development of organ-specific autoimmunity (T1D).
Specific Aim 2. Determine the degree of Fas involvement in Bcell destruction during development of autoimmune diabetes. a. We will determine whether fi-cell-specific deletion of Fas affects the development of spontaneous diabetes in NOD model of T1D; b. We will determine the input of other cytotoxic mechanisms into Fas-dependent and Fas-independent apoptosis of &cells. Our studies will open new venues to regulation of immune responses through controlling the lifespan of APC and to prevention of development of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072627-05
Application #
8005505
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2007-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$368,968
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Varanasi, Vineeth; Avanesyan, Lia; Schumann, Desiree M et al. (2012) Cytotoxic mechanisms employed by mouse T cells to destroy pancreatic β-cells. Diabetes 61:2862-70
Lee, Heung Kyu; Mattei, Lisa M; Steinberg, Benjamin E et al. (2010) In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32:227-39
Stranges, Peter B; Watson, Jessica; Cooper, Cristie J et al. (2007) Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26:629-41
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