Pancreatic islet transplantation represents an important potential therapy for insulin-dependent diabetes. The focus of this project has been to understand the mechanism(s) for the induction of both immunity and tolerance to pancreatic islet allografts. The emphasis of this project has continued to shift towards understanding the latter process, the nature of cellular interactions that result in tolerance inducing in the adult, immunocompetent recipient. Toward this end, the main focus of this renewal application will be to develop a paradigm of induced allograft tolerance and to test the implications of this model. The general working hypotheses of this proposal are threefold: (1) Tolerance induced in adult animals results in dominant regulatory tolerance, (2) Tolerance involves a CD4 T cell-dependent change in the host class-II restricted ('indirect') pathway of allograft recognition, and (3) Apparently distinct strategies of inducing allograft tolerance ultimately employ a common mechanism. While some features of these prepositions may prove to be incorrect, they are intended to provide a clear hypothetical framework to be critically evaluated. That is, experiments described in this application are designed to test (i.e. support or disprove) the implications of these three hypotheses. We have chosen these particular hypotheses because results generated the previous funding period suggest that a CD4-dependent, transferable, donor-specific tolerance can be generated in adult animals without an apparent requirement for eliminating or functionally inactivating relevant, potentially graft-destructive T cells in vivo. A number of implications for the induction and maintenance of potentially regulatory tolerance will be tested by the following specific aims: (I) determine whether tolerance is dominant or recessive, (II) determine the requirements for tolerance induction, and (III) determine the fate of relevant, graft-reactive T cells within a tolerizing environment.
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