Role of cytokines in the pathogenesis of autoimmune IDDM in KRV-infected DR-BB rats

Abstract

The diabetes-resistant DR-BB rat, derived from diabetesprone forebears, does not normally develop spontaneous insulitis or diabetes, but when infected with Kilham rat virus (KRV) this animal develops autoimmune diabetes similar to the diabetes-prone DP-BB rat. KRV infects the lymphoid organs, such as the spleen, thymus, and lymph nodes, but this virus does not infect pancreatic f3-cells, indicating that KRV-induced diabetes in DR-BB rats does not result from direct cytolysis of f3-cells after infection with KRV [1,2].Recent experimental data suggest that KRV infection of DR-BB rats leads to the activation of silent autoreactive T-cells [3]. However, the precise mechanisms by which KRV induces autoimmune insulin-dependent diabetes mellitus (IDDM) without the infection of f3-cells are poorly understood. In this study, we attempted to determine whether macrophages and macrophage-derived cytokines play any role in the development of KRV-induced diabetes in DR-BB rats. 78% of DR-BB rats treated with KRV and Poly I:C develop diabetes, whereas depletion of macrophages with liposome-encapsulated dichioromethylene diphosphonate in KRV and Poly I:C-treated DR-BB rats results in the near complete prevention of insulitis and diabetes. Measurement of the macrophage-derived cytokines IL-12, TNF-a, and IL-1f3 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-y cytokine gene expression closely correlates with an elevation of IL-12, but IL-4 and IL-10 does not change. Depletion of macrophages before the isolation of splenic lymphocytes from DR-BB rats treated with KRV and Poly I:C resulted in the loss of ability to transfer diabetes to young DP-BB rats. On the basis of these observations, we conclude that macrophages and macrophage-derived cytokines play a critical role in the cascade of events leading to the destruction of pancreatic 3-cells, culminating in the development of IDDM.