TRANSGENIC EXPRESSION OF MOUSE PROINSULIN-II PREVENTS DIABETES IN NONOBESE DIABETIC MICE

IDDM in humans and in nonobese diabetic (NOD) mice is a T-cell-depende nt antoimmune disease in which the beta-cells of the pancreatic islets are destroyed, Several putative beta-cell autoantigens have been iden tified, but insulin and its precursor, proinsulin, are the only ones t hat are beta-cell specific, (Pro)insulin may be a keg autoantigen in I DDM. To address the role of proinsulin in the development of IDDM, we generated NOD mice transgenic for the mouse proinsulin II gene driven off a major histocompatibility complex (MHC) class II promoter to dire ct expression of the transgene to MHC class II bearing cells, includin g those in the thymus, with the aim of deleting proinsulin-reactive T- cells, The mononuclear cell infiltration of the islets (insulitis) is almost completely absent, and diabetes is prevented in these transgeni c NOD mice. The mononuclear cell infiltration of the salivary glands ( sialitis) and immune responses to ovalbumin (OVA) are not altered, ind icating that the protective effect of the transgene is specific for is let pathology and not due to general immunosuppression, We conclude th at autoimmunity to proinsulin plays a pivotal role in the development of IDDM.