LONG-TERM GOALS: To improve the results and applicability of islet transplantation early in the course of type 1 diabetes through the attenuation of non-specific inflammatory responses, induction of allo-tolerance, and the restoration of self-tolerance. Unparalleled progress in the conceptual understanding of the mechanisms operative in the induction of allo-tolerance and restoration of self-tolerance has led to the development of selective immunomodulatory strategies. Prime examples of progress made include i) the demonstration of long-term islet allograft survival in non-human primates receiving anti-CD40 Ligand antibody monotherapy, ii) the induction of robust tolerance to murine islet allografts by allo-antigen pretreatment under the cover of short-term anti-CD40L therapy, and iii) the restoration of self-tolerance to beta cell autoantigens in overtly diabetic NOD mice by FcR non-binding anti-CD3 anti bodies. Moreover, blockade of the CD40L/CD40 costimulatory pathway has been shown to prevent inflammatory responses such as cell extravasation, production of inflammatory and chemotactic cytokines, and activation of macrophage effector function. These accomplishments signal a quantum leap in our approaches to circumvent islet graft failure due to non-specific inflammation, autoimmune destruction, and rejection; they now provide realistic opportunities for major advances in clinical islet transplantation. HYPOTHESES: The safety and efficacy of selective immunomodulatory therapies involving FcR non-binding anti-CD3 and anti-CD40L therapy in experimental models of islet transplantation will translate into clinical trials. In addition, implementation of anti-inflammatory, tolerogenic protocols without adverse effects on insulin secretion and action will allow for sustained insulin independence in the majority of type 1 diabetic islet allograft recipients. To test these hypotheses, the incestigators propose the following Specific Aims.
SPECIFIC AIM 1. To establish that induction immunotherapy with the FcR non-binding huOKT3g1 monoclonal antibody prevents autoimmune destruction of human islet grafts.
SPECIFIC AIM 2. To establish that alloantigen pre-treatment under the cover of short-term costimulatory blockade with the anti-CD40L specific monoclonal antibody 5c8 prevents rejection of subsequent human islet allografts.
SPECIFIC AIM 3. To assess the metabolic and immunologic state of islet transplant recipients. The investigators believe that the results of these studies will increase our understanding of the safety, efficacy and underlying mechanisms of selective immunomodulatory therapies aimed at maximizing engraftment and functional survival of allogeneic human islets in type 1 diabetic recipients, and thereby provide a basis for the successful application of minimally invasive means of restoring euglycemia and insulin independence early in the course of diabetes.
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