| Abstract: | 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. |
