REQUIREMENT OF FAS FOR THE DEVELOPMENT OF AUTOIMMUNE DIABETES IN NONOBESE DIABETIC MICE

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell-m ediated autoimmune disease. To investigate the role of Fas-mediated cy totoxicity in pancreatic beta cell destruction, we established nonobes e diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out o f three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respect ively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments wer e performed. When splenocytes were transferred from diabetic NOD, male NODS-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 an d 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotox icity is required to initiate beta cell autoimmunity in NOD mice. Fas- Fas ligand system might be critical for autoimmune beta cell destructi on leading to IDDM.