Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1diabetes in NOD mice

The development of spontaneous autoimmune diabetes in nonobese diabetic (NO D) mice provides for their use as a model of human type 1 diabetes. To test the feasibility of muscle-directed gene therapy to prevent type 1 diabetes , we developed recombinant adeno-associated virus (rAAV) vectors containing murine cDNAs for immunomodulatory cytokines IL-4 or IL-10. Skeletal muscle transduction of female NOD mice with IL-10, but not IL-4, completely abrog ated diabetes. rAAV-IL-10 transduction attenuated the production of insulin autoantibodies, quantitatively reduced pancreatic insulitis, maintained is let insulin content, and altered splenocyte cytokine responses to mitogenic stimulation. The beneficial effects were host specific, as adoptive transf er of splenocytes from rAAV IL-10-treated animals rapidly imparted diabetes in naive hosts, and the cells contained no protective immunomodulatory cap acity, as defined through adoptive cotransfer analyses. These results indic ate the utility for rAAV, a vector with advantages for therapeutic gene del ivery, to transfer immunoregulatory cytokines capable of preventing type 1 diabetes. In addition, these studies provide foundational support for the c oncept of using immunoregulatory agents delivered by rAAV to modulate a var iety of disorders associated with deleterious immune responses, including a llergic reactions, transplantation rejection, immunodeficiencies, and autoi mmune disorders.