beta-cell destruction in NOD mice correlates with Fas (CD95) expression onbeta-cells and proinflammatory cytokine expression in islets

A mechanism of autoimmune destruction of islet beta-cells in type 1 diabete s has been proposed to be the binding of Fas ligand (FasL) on T-cells to Pn s receptors on beta-cells, We investigated this proposal by examining the e xpression of Fast and Fas on islet-infiltrating T-cells and beta-cells in r elation to beta-cell destruction in a syngeneic islet transplant model In N OD mice. Diabetic NOD mice were transplanted with syngeneic islets and inje cted with complete Freund's adjuvant, which prevented diabetes recurrence ( nondestructive insulitis), and with phosphate-buffered saline, which did no t(beta-cell destructive insulitis), Two-color immunohistochemical assays re vealed that Fast was expressed on CD4(+) T-cells, CD8(+) T-cells, and beta- cells in islet grafts from both diabetic and normoglycemic mice, and the pe rcentage of each type of cell that expressed Fast was greater in islet graf ts from normoglycemic compared with diabetic mice, In contrast, Fas was exp ressed on CD4(+) T-cells, CD8(+) T-cells, and beta-cells in islet grafts fr om diabetic mice, but it was nearly or totally absent on these cells in isl et grafts from normoglycemic mice. Similarly, polymerase chain reaction ana lysis of islet grafts revealed that Fas mRNA expression was significantly l ower in islet grafts from normoglycemic compared with diabetic mice. Also, mRNA levels of interleukin (IL)-1 alpha tumor necrosis fatter (TNF)-alpha, and interferon (IFN)-gamma were significantly lower in islet grafts from no rmoglycemic mice. Finally Fas was induced on NOD islet cells by incubation with IL-1 beta, IFN-gamma, and the combination of IL-1 beta, TNF-alpha, and IFN-gamma, These findings support the concept that cytokine-induced Fas re ceptor expression on islet beta-cells is a mechanism for their destruction by Fast-expressing CD4(+) and CD8(+) T-cells and, possibly by Fast-expressi ng beta-cells themselves.