? ? Activation-induced cell death (AICD) in T cells is one of the major mechanisms for peripheral tolerance. Repeated stimulation of T cells via their antigen receptor (TCR) induces coexpression of Fas and Fas ligand (FasL) on the surface of T cells and the FasL interaction leads to the """"""""suicide"""""""" or """"""""fratricide"""""""" of T cells. Proteoglycan (PG) induced arthritis (PGIA) is a novel autoimmune murine model induced by systemic immunization of BALB/c mice with cartilage PG. The development of the disease is based upon cross-reactive immune responses between the immunizing human and mouse (self) cartilage PGs in genetically susceptible BALB/c mice. In this autoimmune arthritis model, an aberrant proliferation of peripheral CD4+ T cells in vitro in response to TCR stimulation is found to be associated with low levels of AICD and a high ratio of interferon-gamma to interleukin-4 (IL-4) in arthritic mice. Moreover, the incidence and severity of PGIA is augmented in IL-4-deficient mice in comparison to wild-type (WT) BALB/c mice, whereas administration of IL-4 to WT BALB/c mice significantly reduces disease. Recent studies indicate that IL-4 can promote AICD by down regulating expression of Fas-associated death domain-like IL1 beta-converting enzyme inhibitory protein (FLIP) and up regulating FasL expression, and these effects are achieved via the up regulation of T cell sensitivity to IL-2. These findings together suggest that T helper 1 (Thl) cells from arthritic mice may be resistant to AICD which may be ascribed to a higher level of FLIP expression. The overall hypothesis of this research proposal is that IL-4 may potentiate peripheral deletion of autoreactive Thl cells in PGIA. The absence of IL-4 may facilitate the accumulation of autoreactive Thl cells in the periphery, leading to the breakdown of self-tolerance, and provoking inflammation in synovial joints by an antigen-driven mechanism. In this research proposal, studies are described to investigate whether and how IL-4 affects AICD of CD4+ T cells in PGIA. Specifically, they will determine whether (i) lack of IL4 results in a severely impaired Fas-mediated AICD of CD4+ T cells in IL-4deficient mice with PGIA; (ii) defective AICD of CD4 T cells in IL-4-deficient mice with PGIA is regulated by an aberrant expression of FLIP and/or FasL; (iii) IL-4-mediated Janus kianses/signal transducer and activator of transcription-6 signaling pathway confers the susceptibility of autoreactive T cells to AICD in PGIA; and (iv) IL-4 regulates the susceptibility of autoreactive T cells to AICD by adjusting the cell cycle progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AR049047-05
Application #
7122026
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2002-09-15
Project End
2007-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2006
Total Cost
$97,200
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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