Harnessing the immunomodulatory properties of Sertoli cells to enable xenotransplantation in type I diabetes

Islet transplantation has emerged as a viable long-term means of treating type I diabetes. This is largely due to the success of the "Edmonton protocol" which has produced insulin independence in 85% of patients 1 year after transplantation of allogeneic islets together with a non-steroid immunosuppressive regimen. While these data provide a clear and unequivocal demonstration that islet transplantation is a viable treatment strategy, the shortage of suitable donor tissue together with the debilitating consequences of life-long immunosuppression necessitate the development of novel means to enable transplantation of all type 1 diabetics including the young juvenile diabetics. One potential means of enabling islet transplantation takes advantage of the ability of Sertoli cells to provide local immunoprotection to co-grafted islets, including those from xenogeneic sources. Sertoli cells are normally found in the testes where one of their functions is to provide local immunologic protection to developing germ cells. In animal models, allogeneic and xenogeneic islets survive and function for extended periods of time when grafted into the testes. Moreover, isolated Sertoli cells protect co-grafted allogeneic and xenogeneic islets from immune destruction and reverse diabetes in immunocompetent and autoimmune animals. These benefits are discussed in the context of several potential underlying biological mechanisms.