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 diabetes, but when infected with Kilham rat virus (KRV) this animal develops 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 KRV-induced diabetes in DR-BB rats. 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-BB rats results in the near-complete prevention of insulitis and diabetes. Measurement of the macrophage-derived cytokines IL-12, TNF-alpha, and IL-1beta 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-4 and IL-10 do 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 beta cells, culminating in the development of insulin-dependent diabetes mellitus.
Chung
Y H
YH
Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, Faculty of Medicine, The University of Calgary, Alberta, Canada.
Jun
H S
HS
Kang
Y
Y
Hirasawa
K
K
Lee
B R
BR
Van Rooijen
N
N
Yoon
J W
JW
D000818:Animals; D001947:Breeding; D016207:Cytokines / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D017992:Parvovirus; D051381:Rats
D016207:Cytokines