Innate immunity in type 1 diabetes.

BACKGROUND: Rat models of diabetes have emerged as a powerful experimental tool for addressing the role of microbial pathogens in the mechanism of autoimmune diabetes. We have used the biobreeding diabetes resistant and LEW1.WR1 rat models to identify the role of virus-induced innate immunity in the mechanism of type 1 diabetes.

METHODS: Groups of rats 21-25 days of age were left untreated, injected i.p. with 1×10(7) PFU of Kilham rat virus (KRV) only, or with 1-3 µg/g body-weight-purified toll-like receptor agonists on three consecutive days and infected with 1×10(7) PFU of KRV on the following day. Spleens and pancreatic lymph nodes were recovered 5 days after infection and used for gene array analysis. To test the role of inflammation in diabetes, rats injected with KRV only or Poly(I:C) plus KRV were also administered with 2 or 0.2 µg/g body weight of dexamethasone and followed for diabetes for 40 days.

RESULTS: KRV induced the expression of a vast array of proinflammatory genes in pancreatic lymph nodes on day 5 following infection. Brief dexamethasone therapy downmodulated inflammation and completely blocked diabetes.

CONCLUSIONS: Our data suggest a strong association between early virus-induced proinflammatory responses and islet destruction and raise the possibility that targeting innate immune pathways in the early stages of diabetes may be a useful strategy for disease prevention.