Islet transplantation can be used to treat type I diabetes, yet persisting alloimmune and autoimmune responses represent major obstacles to clinical success for this procedure. Studies from animal models suggest in a delivery specific-fashion (systemic administration and/or local cellular expression), anti-inflammatory agents can delay/prevent recurrent type I diabetes in islet transplantation. In fact, using rAAV vector mediated gene therapy, we have recently shown that the anti-inflammatory cytokine IL-I 0 completely prevents the development of type I diabetes in NOD mice and recurrent of type I diabetes after syngeneic islet transplantation in NOD mice. Alpha 1 antitrypsin (AAT) and elafin are serine proteinase inhibitors (serpin), and have anti-inflammatory properties. Studies have shown that elafin gene transfer protects against vein graft degeneration. In addition, human hAAT completely abolished the acute inflammatory infiltration. We have recently shown that normal human islets secret AAT and gene transfer of hAAT prevents type 1 diabetes in NOD mice (see preliminary data). Lines of evidence suggest that serpins, namely AAT and elafin, may play important roles in protecting islets from autoimmunity and alloimmnunity. The objective of this application is to test the feasibility of AAT and elafin gene deliveries to enhance islet transplantation.
In Aim 1, murine islets will be ex vivo transduced with rAAV vectors expressing AAT or elafin, prior to transplantation. Our hypothesis is that islet produced AAT and elafin will prevent the islets from recurrent autoimmunity and alloimmune rejection.
In Aim 2, the diabetic recipient animals will be intramuscularly injected with the rAAV vectors before islets transplantation. Our hypothesis is that overexpression of AAT and elafin in the circulation will alter the immunity and protect transplanted islets. Because of the anti-inflammatory, non-toxic features of these transgene products, these approaches may provide new, more practical and safer treatment for type I diabetes. These studies will also provide information vital to understanding the immunoregulatory mechanisms critical to the development of both alloimmune and autoimmune islet cell rejection mechanisms and recurrent type I diabetes.
