A critical factor in early pancreas and islet graft failure in individuals suffering from insulin-dependent diabetes mellitus (IDDM) is recurrent autoimmune- mediated destruction of the insulin producing beta cells. One approach to establish host tolerance to the grafts is to promote beta cell antigen- specific immune deviation. In this way, antigen-specific regulatory Th2 cells are induced to suppress the activity of autoreactive Th1 cells. The investigators and others have shown that this approach is indeed effective in preventing diabetes in the NOD mouse, a murine model for spontaneous IDDM. Furthermore, the applicants have recent evidence demonstrating that an ongoing diabetogenic response can be suppressed in NOD mice treated with the beta cell autoantigen glutamic acid decarboxylase (GAD65). The current challenge, however, is to establish strategies of immune deviation which induce effective, long-term protection in a safe manner. With this in mind, the applicants have developed four specific aims. First, the applicants will determine the phenotype and peptide specificity of GAD65- specific regulatory T cells capable of suppressing ongoing IDDM in NOD mice. Furthermore, the investigators will examine the relative contribution of CD4+ Th2 cells in disease suppression, and the precise mechanism by which this protection is mediated. Second, the applicants will determine whether GAD65- and insulin chain-specific peptide immunotherapy can effectively induce regulatory T cells and suppress ongoing IDDM in NOD mice. Third, the investigators will assess the feasibility of genetic vaccines as a delivery system to induce beta cell antigen-specific regulatory T cells and in turn, prevent and suppress the diabetogenic response. Fourth, the investigators will determine whether beta cell autoantigen-specific induced immune deviation can lead to permanent protection for syngeneic islets grafted in overtly diabetic NOD mice. In addition, the applicants will assess the applicability of antigen-specific immune deviation to suppress an islet allograft response.

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University of North Carolina Chapel Hill
Chapel Hill
United States
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