Lentivirus-mediated transduction of islet grafts with interleukin 4 results in sustained gene expression and protection from insulitis

Autoimmune destruction of islets in the pancreas leads to the development o f insulin-dependent diabetes mellitus (IDDM). Replacement of insulin-produc ing tissue by transplantation of islets provides a cure to disease but requ ires immunosuppression or a means of controlling anti-graft immune response s. To promote islet survival we have utilized a local approach by expressin g immunoregulatory molecules in islet grafts. The results presented here sh ow that the human immunodeficiency virus (HIV)-based lentiviral vector is c apable of stably transducing whole islets, Foreign reporter gene expression was observed both in vitro and in vivo 30 days after transplantation. Graf ts containing insulin-positive beta-islet cells expressing foreign protein indicate that transduction does not interfere with glucose regulation. The absence of inflammatory infiltrates in grafts suggests that transduction do es not activate the immune system, When islets transduced with an HIV vecto r expressing IL-4 were transplanted into diabetes-prone mice, animals were protected from autoimmune insulitis and islet destruction, As demonstrated by proliferative and cytokine analysis, protection was consistent with a sw itching of islet-antigen-specific T cell responses toward a Th2 phenotype. These results suggest that HIV-based lentivirus vectors can efficiently tra nsduce islet cells with genes encoding potentially therapeutic molecules, f or possibly managing diabetes.