Cellular and molecular changes accompanying the progression from insulitis to diabetes

Insulin‐dependent diabetes mellitus (IDDM) is not a disease of unbridled destruction. The autoimmune attack on pancreatic beta cells has two distinct stages – insulitis and diabetes – and progression of the former to the latter appears to be highly regulated. Identifying the factors controlling this transition has been difficult because it is a complex process that occurs non‐universally and asynchronously. We have overcome these difficulties by coupling a simplified TCR transgenic (tg) model of IDDM and the immunosuppressive drug cyclophosphamide (CY). Young BDC2.5 TCR tg mice show insulitis but not diabetes; CY treatment provoked diabetes in 100 % of animals with rapid, highly reproducible kinetics. This allowed a detailed temporal analysis of changes in cellular organization and cytokine gene expression within the lesion. The monokines IL‐18, IL‐12 and TNF‐α were pivotal, their induction occurring almost immediately and their coordinate action being required for the onset of aggression. Other cytokines with direct toxicity for beta cells, including IL‐1‐β, IL‐6 and IFN‐γ, were subsequently induced; in contrast, there was no cellular or molecular evidence of cell contact‐mediated mechanisms of beta cell death.