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.