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 immunosuppressant, leflunomide (Lef), can prevent allogeneic and xenogeneic islet graft rejection in streptozocin (STZ)-induced diabetic animals. However, whether Lef required to prevent islet graft rejection is sufficient to prevent the recurrence of autoimmune diabetes has not been addressed. METHODS: The effect of Lef on concordant xenogeneic islet graft in STZ-induced diabetic mice and autoimmune nonobese diabetic (NOD) mice 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 diabetic NOD mice were investigated. RESULTS: In STZ-induced diabetic BALB/c mice, Lef treatment significantly prolonged rat islet graft survival. However, Lef could not significantly prolong rat islet graft survival 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, when 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 mice islet graft survival in NOD mice. CONCLUSIONS: Lef preventing concordant xenogeneic islet graft rejection is not sufficient to prevent the recurrence of autoimmune diabetes in NOD mice. We believe that controlling autoimmunity after islet transplantation will lead the way to promote successful clinical islet transplantation in the future.