Prevention and cure of autoimmune diabetes in nonobese diabetic mice by continuous administration of FTY720

Background. Treatment of nonobese diabetic (NOD) mice with FTY720 before the development of insulitis prevents the onset of diabetes. In this study, the authors investigated whether FTY720 treatment of NOD mice with established insulitis prevents the development of diabetes. Methods. FTY720 (1 mg/kg) was administered continuously to euglycemic NOD mice starting at 14 or 23 weeks of age. A group of untreated, age-matched NOD mice served as controls. Mice with more than 300 mg/dL blood glucose on three consecutive measurements were considered diabetic. Results. Diabetes developed in control mice starting at 13 weeks of age and reached 78% by 33 weeks of age. Mice at 14 and 23 weeks of age exhibited extensive insulitis that progressed with age. Continuous oral administration of FTY720 starting at either age completely prevented the development of diabetes. However, its withdrawal at 37 weeks of age led to abrupt diabetes onset. Pancreases of FTY720-treated diabetes-free mice showed peripheral insulitis, with strong insulin staining. The protection from diabetes was also achieved by intraperitoneal injection of FTY720 or sirolimus (1.5 mg/kg). Unlike FTY720, withdrawal of sirolimus did not induce diabetes. Continuous oral FTY720 (3 mg/kg) treatment in overtly diabetic NOD mice led to complete reversal of diabetes in 6 of 11 mice. The standard adoptive transfer study in NOD-severe combined-immunodeficient mice showed that peripheral lymphoid organs of FTY720-treated mice contained diabetogenic cells but not dominant immunoregulatory cells. Concl usions. FTY720, which does not cause generalized immunosuppression, may be a safe and benign therapeutic agent for chronic use to prevent or cure type I diabetes.