Poly I:C Induction of α-Interferon in the Diabetes-Prone BB and Normal Wistar Rats: Dose-Response Relationships

Abstract

Although the administration of a fixed dose of the alpha-interferon (alpha-IFN) inducer, polyinosinic polycytidilic acid (poly I:C), accelerates the development of diabetes in DP-BB rats, no reports have characterized the dose-response relationship of poly I:C with serum alpha-IFN levels and the development of diabetes. This study examines the dose-response relationships of poly I:C with the induction of serum alpha-IFN and the development of diabetes in DP-BB and normal Wistar rats. Also tested in this study is the hypothesis that the lack of development of diabetes in poly I:C-treated normal Wistar rats is attributable to a deficient alpha-IFN response. Using poly I:C doses of 0.5, 1.5, 5, and 10 micrograms/g body weight, a direct dose-response relationship was observed in DP-BB rats with the serum alpha-IFN response. Moreover, all doses of poly I:C accelerated the onset of diabetes in BB rats. Serum alpha-IFN levels inversely correlated with time of onset of diabetes (P < 0.01). Also, BB rats with higher levels of serum alpha-IFN were associated with earlier onset of diabetes (P < 0.001). Poly I:C-induced serum alpha-IFN levels were significantly lower in diabetic than in nondiabetic BB rats. In normal Wistar rats, although all doses of poly I:C significantly increased serum alpha-IFN levels, diabetes was not induced. The results of this study indicate that poly I:C administration elevates serum alpha-IFN and accelerates the development of diabetes in BB rats at even very low doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats

“…However, Poly IC increased serum IFN-a in WF rats to concentrations equal to or greater than those found in BB-DP rats and induced diabetes in the BB-DP, but not the WF animals [13]. Interferon-a could be rate-limiting, however, if its cellular uptake or metabolism varies between strains.…”

“…Poly IC induces circulating IFN-a in BB-DP/Wor and WF rats [13], and this cytokine is believed to play a part in the pathogenesis of Type I diabetes. However, Poly IC increased serum IFN-a in WF rats to concentrations equal to or greater than those found in BB-DP rats and induced diabetes in the BB-DP, but not the WF animals [13].…”

Rat Models of Type 1 Diabetes: Genetics, Environment, and Autoimmunity

“…Higher doses of poly I:C (10 g/g) induce diabetes in nearly all BBDR/Wor rats . Parenthetically, highdose poly I:C accelerates diabetes in the BBDP/Wor rat Sobel et al 1995), an effect associated with increased levels of IFN-␣ (Sobel et al 1994). At lower doses, it is protective (Sobel et al 1998b).…”

“…The primate equivalent of the rat ART2 gene is a pseudogene (Haag et al 1994). BBDP/Wor rat diabetes can also be prevented by intrathymic transplantation of islets (Posselt et al 1992) and low doses of the TLR3 ligand polyinosinic:polycytidylic acid (poly I:C 1 ) (Sobel et al 1998b), but high dose poly I:C accelerates diabetes (Sobel et al 1994). The relevance of these preventive strategies to human diabetes is not yet clear.…”

Immunobiology of Cardiac Allograft and Xenograft Transplantation

“…For example, we found that purified CD4+ T cells are sufficient for inducing rapid rejection of rat islet 55 and heart xenografts in scid mice_ Furthermore, we found that CD4+ T cells transferred equal islet xenograft rejection kinetics in either NKsufficient or NK-deficient scid-beige mice (unpublished observations). Conversely, in the absence of T cells, activation of NK activity by poly I:C induction 170 does not trigger destruction of rat islet xenografts established in scid mice. That is, intentional activation of systemic NK activity is not sufficient for the rejection of islet xenografts.…”