インスリン依存型糖尿病の発症機構に関する研究 : 自己免疫性糖尿病の初期反応における接着分子の役割

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  • Studies on Pathogenesis of Insulin-dependent Diabetes Mellitus : The role of the Adhesion Molecules on Initial Events in Autoimmune Diabetes

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In the present study, to analyze the role of several adhesion molecules in the early age of NOD mice, short-term treatment with monoclonal antibodies(mAbs) against these molecules were performed. When mAbs against leukocytes function-associated antigen-1 (LFA-1) and intercelluar adhesion molecule-1 (ICAM-1) were administrated for only 6 days at 2 wk of age, neither diabetes nor insulitis was observed at 30 wk of age. However, anti-LFA-1/ICAM-1 treatment at 10 wk of age could not prevent overt diabetes. In contrast, administration of anti-CD80/CD86 mAbs at 2 wk or 10 wk of age accelerated the development of diabetes. The treatment with anti-CD80 mAb alone also resulted in an accelerated onset of diabetes. These results suggested that the tolerance against β cell antigen(s) was induced only when LFA-1/ICAM-1 pathway was transiently blocked at 2 wk of age. Protective suppressor activity was not explicable for the tolerance since splenocytes from anti-LFA-1/ICAM-1 mAbs-treated NOD mice had a little suppressive effect in the adoptive transfer experiments. Although these splenocytes could not transfer the insulitis and subsequent diabetes to NOD-scid mice, the absence or the inactivation of diabetogenic effector T cells could not also explain the tolerance, since splenic T cells from treated mice preserved proliferaive responses to islet cell antigens and glutamic acid decarboxylase 65 in vitro. These results suggest that an unique peripheral tolerance was induced by the transient blockade of LFA-1/ICAM-1 pathway in early age of NOD mice and also suggest the possibility that LFA-1/ICAM-1 pathway would be an essential component of the initial events in autoimmune diabetes.

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