NEONATAL TOLERIZATION WITH GLUTAMIC-ACID DECARBOXYLASE BUT NOT WITH BOVINE SERUM-ALBUMIN DELAYS THE ONSET OF DIABETES IN NOD MICE

To test the role of glutamic acid decarboxylase (GAD(65)) or bovine se rum albumin (BSA) autoimmunity in the pathogenesis of diabetes, GAD(65 ) or BSA was injected intraperitoneally into neonatal female NOD mice (100 mu g/mouse of each protein). Treatment with GAD(65), but not with BSA, significantly delayed the onset of diabetes compared with contro l mice (P < 0.05). At 18 weeks, 6 of 10 control mice compared with 0 o f 10 GAD(65)-treated mice (P = 0.005) and 7 of 14 BSA-treated mice had developed diabetes. However, after 79 weeks, 6 of 10 of the GAD(65)-t reated mice were diabetic compared with 9 of 10 of the control mice an d 12 of 14 of the BSA-treated mice. In GAD(65)-treated mice without di abetes, insulitis was markedly reduced compared with control or BSA-tr eated mice (P < 10(-4)). To further elucidate why GAD becomes an autoa ntigen, the expression in NOD mice islets was studied. Quantitative im munohistochemistry revealed that islet cell expression of GAD was incr eased in 5-week-old NOD mice compared with BALB/c mice (P = 0.02). Wit h the occurrence of insulitis (9-15 weeks), the GAD expression was fur ther increased relative to 5-week-old NOD mice (P < 0.02). In conclusi on, GAD, but not BSA, autoimmunity is important for the development of diabetes in NOD mice. Furthermore, concordant with the appearance of insulitis, the GAD expression increased in NOD mouse islets, which cou ld possibly potentiate the P-cell-directed autoimmunity.