ROLE OF MACROPHAGES AND MACROPHAGE-DERIVED CYTOKINES IN THE PATHOGENESIS OF KILHAM-RAT-VIRUS-INDUCED AUTOIMMUNE DIABETES IN DIABETES-RESISTANT BIOBREEDING RATS

The diabetes-resistant BioBreeding (DR-BB) rat, derived from diabetes- prone forebears, does not normally develop spontaneous insulitis or di abetes, but when infected with Kilham rat virus (KRV) this animal deve lops autoimmune diabetes similar to the diabetes-prone BioBreeding (DP -BB) rat. In this study, we attempted to determine whether macrophages and macrophage-derived cytokines play a role in the development of KR V-induced diabetes in DR-BB Fats, Seventy-eight percent of DR-BB rats treated with KRV and poly(I:C) develop diabetes, whereas depletion of macrophages with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP) in KRV and poly(I:C)-treated DR-BE rats results in the n ear-complete prevention of insulitis and diabetes, Measurement of the macrophage-derived cytokines IL-12, TNF-alpha, and IL-1 beta revealed a selective increase of their expression, after KRV infection, in the splenic lymphocytes and the pancreatic islets, Measurement of CD4(+) T cell-derived cytokines revealed that IL-2 and IFN-gamma cytokine gene expression closely correlates with an elevation of IL-12, but IL-il a nd IL-10 do not change. Depletion of macrophages before the isolation of splenic lymphocytes from DR-BE rats treated with KRV and poly(I:C) resulted in the loss of ability to transfer diabetes to young DP-BB ra ts, On the basis of these observations, we conclude that macrophages a nd macrophage-derived cytokines play a critical role in the cascade of events leading to the destruction of pancreatic beta cells, culminati ng in the development of insulin-dependent diabetes mellitus.