The success of islet transplantation therapy for Type I diabetes mellitus (T1DM) depends on its ability to control both T cell-mediated alloreactivity and the ?-cell autoimmunity. Inducible costimulator (ICOS)/B7-related protein 1(B7RP-1) signaling is crucial for regulation of effector Th1 and Th2 cell function. Treatment with ICOS antagonist inhibits Th1 and Th2 mediated inflammation, EAE, allergic airway disease, and mucosal inflammatory disease, and protects allogeneic heart grafts from immunorejection. We hypothesize that genetic modification of the islets to locally express soluble ICOS-Ig may protect the islet-grafts from immunorejection. The mechanism(s) underlying this protection may involve the inactivation of effector T cells by promoting their apoptosis and/or anergy. We will use recombinant adeno-associated virus (rAAV) to deliver the ICOS-Ig or other control genes to the islet cells. AAV is a non-pathogenic virus and has little immunogenicity, may therefore be safe in clinical applications. Recent studies have demonstrated that genetic modification of the islets by rAAV transduction results in the long-term expression of reporter genes in vivo, which does not interfere with insulin production. Finally, the local expression of ICOS-Ig may not affect systemic immunological function, providing a safe means to prolong transplanted islet survival. Therefore, immunotherapy based on transplantation with ICOS-Ig expressing islets to inhibit effector T cells may be especially effective for maintaining syngeneic and allogeneic islet-graft tolerance.In this application, we will: 1). optimize conditions for generation of genetically modified mouse islets which express costimulation inhibitor ICOS-Ig; 2). examine whether transplantation of ICOS-Ig expressing syngeneic and allogeneic islets prevents the recurrence of diabetes; and 3). determine the action of ICOS-Ig in the functional maintenance of transplanted islets. These studies will address fundamental questions concerning the regulatory function of ICOS/B7RP-1 signaling on alloreactive and autoimmune T cell responses. Our findings may provide the basis for novel immunotherapies for the prevention and inhibition of immunorejection of islet grafts in man.
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