In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha

The islet-infiltrating and disease-causing leukocytes that are a hallmark o f insulin-dependent diabetes mellitus produce and respond to a set of cytok ine molecules. Of these, interleukin 1 beta, tumor necrosis factor (TNF)-al pha, and interferon (IFN)-gamma are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to beta cell apopt osis and diabetes at multiple points. To understand how these cytokines inf luence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion : the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-indu ced effector molecules to assess how these compartmentalized loss-oi-functi on mutations alter the events leading to diabetes. We found that islets def icient in Fas, IFN-gamma receptor, or inducible nitric oxide synthase had n ormal diabetes development; however, the specific lack of TNF-alpha recepto r 1 (p55) afforded islets a profound protection front disease by altering t he ability of islet-reactive, CD4(+) T cells to establish insulitis and sub sequently destroy islet beta cells. These results argue that islet cells pl ay a TNF-alpha-dependent role in their own demise.