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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.