Type I diabetes mellitus is an autoimmune disease that destroys the insulin-producing cells of the pancreas. This disease affects an estimated one million Americans and usually finds its onset in childhood or in young adulthood. It significantly impairs the quality of live and thus puts a significant economic burden on the families of the afflicted. The transplantation of insulin-producing human allogeneic pancreatic islets has been as a curative treatment of the disease. However, the many complications of present immune suppressive therapy are especially grave for the young patients afflicted with type 1 diabetes. Yet, they would especially benefit from pancreatic islet transplantation. Therefore, it is especially important for these young patients to develop novel immune suppression protocols that induce long-term unresponsiveness, if not tolerance, towards the graft and that are short-term and non-toxic. We will discuss in this application how veto immune inhibition can be adapted to induce long-term acceptance of allogeneic grafts. Our arguments are based on the following experimental observations. We had produced Adenoviral vectors that efficiently transferred the expression of the CD8 a-chain to different tissues. These vectors induced efficient, yet specific inhibition T lymphocytes both in vitro and in vivo. In additional experiments, we could demonstrate that these Adenoviral vectors permanently protected fully allogeneic pancreatic islet grafts from rejection. A short-term ex vivo conditioning of the transplant was sufficient to prevent their rejection and thus to permit their long-term survival in normal, non-immune compromised mice. We now propose to produce clinical correlates of such veto vectors, to test their efficacy and toxicity in mouse models of pancreatic islet transplantation and to expand these transplantation studies into mice suffering from autoimmune diabetes, i.e. into non-obese diabetic (NOD) mice.
