IFN-GAMMA ACTION ON PANCREATIC BETA-CELLS CAUSES CLASS-I MHC UP-REGULATION BUT NOT DIABETES

We have generated transgenic nonobese diabetic (NOD) mice expressing d ominant negative mutant IFN-gamma receptors on pancreatic beta cells t o investigate whether the direct effects of IFN-gamma on beta cells co ntribute to autoimmune diabetes. We have also quantitated by flow cyto metry the rise in class I MHC on beta cells of NOD mice with increasin g age and degree of islet inflammatory infiltrate. Class I MHC express ion increases gradually with age in wild-type NOD mice; however, no su ch increase is observed in the transgenic beta cells. The transgenic m ice develop diabetes at a similar rate to that of wild-type animals. T his study dissociates class I MHC upregulation from progression to dia betes, shows that the rise in class I MHC is due to local IFN-gamma ac tion, and eliminates beta cells as the targets of IFN-gamma in autoimm une diabetes.