Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice.

作者：Iain Leslie Campbell, Thomas W. H. Kay, Leonie Oxbrow, Leonard Charles Harrison · 发表于：Journal of Clinical Investigation · 年份：1991 · DOI：10.1172/jci115055 · 被引用次数：375 · 研究领域：Diabetes and associated disorders、Diabetes Management and Research、Pancreatic function and diabetes

Experimental studies in vitro suggest that cytokines are impor- tant mediators in the pathogenesis of autoimmune insulin-de- pendent diabetes mellitus (IDDM).However, there is little evidence for the role ofcytokines in vivo, either in humans or in the spontaneous animal models of IDDM such as the NOD mouse or BB rat.To address this question, we used the model ofcyclo- phosphamide (CYP)-induced autoimmune diabetes in the NOD/Wehi mouse to examine for (a) the production of IFN-'y and IL-6 from isolated islets, and (b) the effect of anti IFN-'y or anti IL-6 monoclonal antibodies on the development of dia- betes.After cyclophosphamide, the majority of these mice de- velop of mononuclear cell infiltrate (insulitis) which by 10-14 d is associated with beta cell destruction.IFN-y activity at low levels (2.7±0.3U/ml) could be detected only in culture super- natants from islets isolated at day 7 post-cyclophosphamide.In contrast, IL-6 activity progressively increased from 457±44 U/ml at day 0 to 6,020±777 U/ml at day 10.Culture of islets with anti-CD3 monoclonal antibody resulted in a significant increase in IFN-'y activity from 41±7 U/ml at day 0 to 812±156 U/ml at day 10.Mice given either anti-IFN-y or anti- IL-6 antibody had a significantly reduced (P < 0.001) incidence of diabetes and especially with IFN-'y, decreased severity of insulitis.We conclude that IFN-y and IL-6 have essential roles in the pathogenesis of pancreatic islet beta cell destruction in this model.(J.Clin.Inves...