IMMUNOMODULATORY STRATEGIES IN AUTOIMMUNE GASTRITIS

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Many autoimmune diseases appear to be mediated by antigen-specific T cells that produce the pro-inflammatory cytokines, IFNgamma and TNFalpha. It would be of great value to develop a strategy to specifically downregulate or eliminate these autoreactive T cells without interfering with other immune functions. The goal of this grant proposal is to study the mechanisms that are involved in two strategies designed to specifically downregulate the activity of antigen-specific T cells and to test these strategies in a well-characterized murine model of autoimmune disease. Previous studies have demonstrated that antigen presenting cells (APCs) pulsed with antigen in the presence of TGFbeta2 transmit a potent tolerance-inducing signal to the peripheral immune system when injected intravenously into naive mice. Accumulating evidence suggests that CD4 and CD8 regulatory T cells are induced and mediate antigen-specific tolerance in this system. The goal of the first specific aim is to understand the mechanisms involved in tolerance induced by TGFbeta-treated APCs. In this aim, the role that regulatory T cells play in this system of tolerance as well as their general mechanism(s) of action will be examined in in vivo studies using knock-out mice, neutralizing antibodies and a TCR transgenic T cell transfer system. Further studies will involve in vitro analyses of the precise mechanisms utilized by regulatory T cells to downregulate effector T cell function. The goal of the second specific aim is to investigate the therapeutic potential of TGFbeta-treated APCs using a murine model of autoimmune gastritis. Neonatal thymectomy (Tx-3) in BALB/c mice induces an autoimmune gastritis that markedly resembles human pernicious anemia. Tile T cell response has been well characterized in this model and is Th1-type cytokine-mediated and targeted to the alpha and beta subunits of H/K ATPase of parietal cells. This aim is designed to determine whether treatment of Tx-3 mice with ATPase-pulsed TGFbeta-treated APCs can "cure" or ameliorate autoimmune gastritis and to characterize the T cell response that is associated with this treatment. The goal of the third specific aim is to explore the ability of FasL-expressing APCs to treat autoimmune disease either independently or as a supplement to treatment with TGFbeta-treated APCs. This aim is designed to characterize the T cell response after activated T cells have been targeted for elimination in vivo by treatment with antigen-pulsed APCs genetically engineered to express FasL. This strategy may be used in conjunction with TGFbeta-treated APCs to successfully treat established autoimmune disease.