IMMUNOSUPPRESSION PREVENTING CONCORDANT XENOGENEIC ISLET GRAFT-REJECTION IS NOT SUFFICIENT TO PREVENT RECURRENCE OF AUTOIMMUNE DIABETES IN NONOBESE DIABETIC MICE

Background. We and others have reported previously that the immunosupp ressant, leflunomide (Lef), can prevent allogeneic and xenogeneic isle t graft rejection in streptozocin (STZ)-induced diabetic animals. Howe ver, whether Lef required to prevent islet graft rejection is sufficie nt to prevent the recurrence of autoimmune diabetes has not been addre ssed. Methods. The effect, of Lef on concordant xenogeneic islet graft in STZ-induced diabetic mice and autoimmune nonobese diabetic (NOD) m ice were studied. Then, whether Lef prevents the onset of spontaneous diabetes in young NOD mice and the recurrence of diabetes after major histocompatibility complex (MHC)-matched islet transplantation in diab etic NOD mice were investigated. Results. In STZ-induced diabetic BALB /c mice, Lef treatment significantly prolonged rat islet graft surviva l. However, Lef could not significantly prolong rat islet graft surviv al in autoimmune diabetic NOD mice. For prevention studies, treatment with Lef at 30 mg/kg/day from 4 weeks to 20 weeks of age significantly reduced the incidence of spontaneous diabetes in NOD mice. However, w hen the NOD mice were treated from 8 to 24 weeks of age, the incidence of spontaneous diabetes was not significantly reduced as compared to the incidence of diabetes in the untreated female NOD mice at 28 weeks of age. Finally, in the MHC-matched islet transplant model, Lef could not significantly prolong MHC-matched nonobese diabetes-resistant mic e islet graft survival in NOD mice. Conclusions. Lef preventing concor dant xenogeneic islet graft rejection is not sufficient to prevent the recurrence of autoimmune diabetes in NOD mice. We believe that contro lling autoimmunity after islet transplantation will lead the way to pr omote successful clinical islet transplantation in the future.