T cell mediated injury to islet allografts

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DESCRIPTION (provided by applicant): Pancreatic islet transplantation has shown increasing efficacy as a therapy for Type I diabetes. However, islet transplants are subject to two potentially distinct immune obstacles: (1) Conventional transplantation rejection and, (2) Recurrence of established autoimmune pathogenesis Previous studies suggest that the predominant effector cell for allograft immunity is the class I MHC-restricted CD8 T cell while the predominant pathway for autoimmune disease recurrence appears to require the class II MHC-restricted CD4 T cell. The chief goal of this proposal will be to determine the relative contribution of major candidate effector pathways of islet injury mediated by defined alloreactive or autoreactive T cells in vivo. The general premise of this proposal is that the effector mechanism(s) of islet damage inflicted by alloreactive CD8 T cells is distinct from islet-specific, autoimmune (islet-specific) CD4 T cells in vivo. In particular, we will test implications of the working hypothesis that CD8 T cell-mediated islet rejection requires a direct, cognate interaction with the target islet cell while the pathogenesis of CD4 islet-specific T cells involves the indirect recognition of islet-associated antigens presented by MHC class II-bearing antigen-presenting cells (APCs). Dissecting the role of these two types of graft-reactive T cells requires a model in which each pathway can be studied independently. To accomplish this, we propose to continue studies using defined T cell receptor (TcR)-transgenic mice with specificities representative of alloreactive CD8 T cells (2C) or islet-specific CD4 T cells (BDC2.5). This proposal has the focus of systematically comparing these two types of islet-destructive T cells for their respective requirements for inflicting injury to pancreatic islet transplants. In particular, we proposed to determine the relative requirement for cytolytic versus inflammatory mechanisms of islet damage. The ultimate application of such results will be to develop strategic combinational therapies that will attenuate rate-limiting pathways of both alloreactive and autoimmune pathways of graft damage.