LOW-DOSE POLY I-C PREVENTS DIABETES IN THE DIABETES-PRONE BB RAT

Poly I:C, an inducer of IFN-alpha and other cytokines, has been used t o study the development of diabetes in both the BioBreeding (BB) diabe tes prone rat and non-obese diabetic (NOD) mouse animal models of insu lin-dependent diabetes mellitus (IDDM). Surprisingly, poly I:C acceler ates the disease in the BB rat while inhibiting it in the NOD mouse. S ince cytokines can have dose related opposing effects on immune respon ses, we hypothesized that the paradoxical effect of polyinosinic polyc ytidylic acid (poly I:C) on diabetes in the two animal models is dose related. Accordingly, we compared the incidence of diabetes and degree of insulitis in diabetes prone BB rats administered saline and poly I :C at doses (0.05 mu g/g body weight and 0.1 mu g/g body weight) up to 100-fold lower than doses (poly5 mu g/g) previously found to accelera te diabetes. In addition, the non-specific suppressor activity of mono nuclear splenocytes from BB rats administered low dose (poly-0.05 mu g /g body weight), high dose (poly-5 mu g/g body weight), and saline wer e compared. The development of diabetes was inhibited in rats treated with each dose of poly I:C. The degree of insulitis in poly-I:C treate d animals was also less severe. The total white blood cell count and p roportion of RT6(+) T-cells and each T-cell subset were unaltered by p oly I:C. When compared to splenocytes of control animals, splenocytes from poly I:C (0.05 mu g/g body weight) treated rats suppressed respon der cell proliferation to concanavalin A and alloantigen. However, spl een cells from high dose poly-I:C did not suppress responder cell prol iferation to alloantigen. In adoptive transfer studies, the administra tion of spleen cells from poly-0.05 treated rats decreased the develop ment of diabetes in recipient BB rats. In vitro studies also demonstra ted that poly-I:C inhibits the proliferative response of BB rat spleen cells to concanavalin A. The administration of poly-0.05, but not pol y-5.0, decreased TNF-alpha mRNA and IL-10 mRNA content in spleen cells . We conclude that poly I:C, at a dose 100 times lower than that requi red to accelerate diabetes prevents the development of diabetes in BB rates by interfering with the development of insulitis. The induction of suppressor cell activity induced by low dose poly-I:C in vivo and t he inhibition of T-cell responses by poly-I:C in vitro suggests that t he diabetes sparing activity of poly I:C is mediated by augmented immu noregulatory cell activity. Further studies with poly I:C may be impor tant in increasing our understanding of the pathogenesis of IDDM and p rovide a means to prevent it. (C) 1998 Academic Press.