IMMUNE-RESPONSE TO GLUTAMIC-ACID DECARBOXYLASE CORRELATES WITH INSULITIS IN NONOBESE DIABETIC MICE

KNOWING the autoantigen target(s) in an organ-specific autoimmune dise ase is essential to understanding its pathogenesis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lym phocytic infiltration of the islets of Langerhans (insulitis) and dest ruction of insulin-secreting pancreatic beta-cells1. Several beta-cell proteins have been identified as autoantigens, but their importance i n the diabetogenic process is not known2. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM3. Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a pa nel of five murine beta-cell antigens and find that antibody and T-cel l responses specific for the two isoforms of glutamic acid decarboxyla se (GAD) are first detected in 4-week-old NOD mice. This GAD-specific reactivity coincides with the earliest detectable response to an islet extract, and with the onset of insulitis. Furthermore, NOD mice recei ving intrathymic injections of GAD65 exhibit markedly reduced T-cell p roliferative responses to GAD and to the rest of the panel, in additio n to remaining free of diabetes. These results indicate that the spont aneous response to beta-cell antigens arises very early in life and th at the anti-GAD immune response has a critical role in the disease pro cess during this period.