Long-term survival of islet allografts in spontaneously diabetic BB rats without chronic immunosuppression

Chemically induced diabetes mellitus in rats can be reversed by pancreatic islet transplantation. We have previously reported that ultraviolet irradiation of rat islets combined with a three-day course of cyclosporin (CyA) starting at the time of grafting reverses the hyperglycemia in strongly histoincompatible rats made diabetic by streptozotocin. Such a protocol also results in long-term rat islet xenograft survival in mice made diabetic by streptozotocin. Since human type I diabetes has a major autoimmune component, transplanted islets may be susceptible to autoimmune destruction similar to that seen in native islets. Autoimmune recurrence of this type has been described in several other systems including, renal transplants between identical twins performed for glomerulonephritis and more recently in pancreatic transplants between identical twins. The BB/W rat appears to be, at present, the best animal model of IDDM. Hyperglycemia occurs spontaneously at 60 to 150 days of age in 60% to 80% of animals and the animals remain nonobese, are ketosis prone and insulin dependent. The native islets of Langerhans develop both a severe mononuclear cell infiltrate (insulitis) and the animals develop circulating anti-islet cell antibodies. Diabetes in BB rats has been prevented or delayed by various immunologic manipulations including: CyA, ALS, neonatal thymectomy, and neonatal bone marrow inoculation. The expression of diabetes is associated with the RT1(u) gene and diabetes can be passively transferred to MHC-matched, immunosuppressed, non-diabetes prone recipients by inoculation of splenic lymphocytes from affected animals. Although the specific mechanism of beta cell destruction in the BB rat requires further clarification, autoimmunity plays a major role in its etiology. In this study, we show that combination of donor islet treatment with UVB irradiation and brief peritransplant treatment of the recipient results in indefinite survival of islet allografts despite the autoimmune nature of diabetes mellitus in the BB rat.