INHIBITION OF DIABETES BY AN INSULIN-REACTIVE CD4 T-CELL CLONE IN THENONOBESE DIABETIC MOUSE

A cloned Th1 cell line was isolated from pancreatic lymph nodes of NOD mice that carries a T-cell receptor encoding V beta 14 and proliferat es in response to NOD islets, islet supernatant, and crystalline bovin e and rat insulin, specifically to a B-chain peptide bound to IA(g7). The response to islet supernatant was reduced by 75% by anti-insulin a ntibody treatment. The insulin-reactive clone reduced insulitis and to tally blocked the development of spontaneous diabetes in NOD mice (n = 8) as well as the adoptive transfer of diabetes into irradiated NOD m ice following the injection of splenocytes from diabetic mice (n = 13) . Trafficking of the adoptively transferred cells was assessed by labe ling the clone or diabetic splenocytes with a fluorescent marker (DiI) . The labeled clone was detected in the islet periphery, whereas label ed splenocytes alone invaded the islets by 3 days. In contrast, the pr otective clone dramatically delayed and reduced the number of labeled diabetic splenocytes infiltrating the islet, although their appearance in the spleen was unaffected. In vitro, the clone as well as supernat ant derived from the clone blocked the proliferation of diabetic NOD s plenocytes to islets. This inhibitory effect was diminished by anti-tr ansforming growth factor-beta. In conclusion, an insulin-specific Th1 cell was isolated from NOD mice that traffics to the islet and prevent s the spontaneous development and the adoptive transfer of diabetes. I t appears to act locally by releasing transforming growth factor-beta and/or other factors that inhibit homing to and/or proliferation of di abetic splenocytes within the islet. These findings may provide insigh ts into and suggest mechanisms for the protective effects of insulin t herapy against diabetes.