The objective of this study is to continue to examine the cellular mechanisms of the autoimmune destruction of pancreatic islets in the spontaneously diabetic BB/W rat, with the eventual goal of developing therapeutic interventions to prevent IDDM in native or transplanted pancreatic islets. With the accumulating evidence suggesting the similarity between the pathogenesis of IDDM in man and the BB/W rat we plan to develop a better understanding of islet (beta cell) destruction in the BB/W rat and develop methods for specific immunologic modulation of this autoimmune disease by 1) isolation and characterization of cytolytic and non-cytolytic effector cell clones; 2) study of migration patterns of effector cells; 3) passive induction of diabetes using effector cell clones; 4) study of disease recurrence in islets transplanted into BB/W rats in relation to their MHC compatibility; 5) generation of new monoclonal antibodies against islet-specific effector cells to block the destructive action of such cells and 6) use of available cross-reacting monoclonal antiidiotypic antibodies to rat Class II antigens as an immunotherapeutic approach in preventing IDDM in BB/W rats. This proposal will focus on the modulation of IDDM in the BB/W rat and in islet transplantation by examining the issue of MHC restriction, and by exploring the use of newly developed monoclonal antibodies directed to antigen receptors on the islet- specific lymphocyte clones, as well as cross-reacting anti-MHC Class II antiidiotypic antibodies to block the autoimmune destruction of both native and transplanted beta cells. The newly developed cell lines and the reagents should be useful to all working on the etiology of autoimmune diabetes mellitus in various models. The overall goal of these closely interdependent experiments remains to clarify the nature of beta cell destruction in native and transplanted islets in the BB/W rat to eventually facilitate successful clinical pancreatic and islet transplantation.
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