Poly I:C Induces Development of Diabetes Mellitus in BB Rat

Abstract

Polyinosinic polycytidilic acid (poly I:C), an inducer of alpha-interferon, accelerates the development of diabetes in diabetes-prone (DP) BioBreeding (BB) rats. This study investigates the effect of administering poly I:C to a diabetes-resistant (DR) strain of BB rats. We compared the incidence of diabetes, the degree of insulitis, the number of NK cells, helper-inducer cells, cytotoxic-suppressor cells, Ia+ T cells, RT6.1+ T cells, and NK cell bioactivity in DR rats treated with saline and with a 5 micrograms/g body wt (poly-5) dose and a 10 micrograms/g body wt (poly-10) dose of poly I:C. The incidence of diabetes was also compared with that of DP rats receiving poly-5. We found that both doses of poly I:C significantly induce the development of diabetes in the DR BB rat. However, treatment of DR rats with the higher dose induces a greater rate of development of diabetes and earlier onset of diabetes than the lower poly-5 dose. The rate of diabetes development and the mean age of onset were similar in poly-10-treated DR and poly-5-treated DP rats. A significant degree of insulitis occurred in all the poly I:C-treated DR rats, even those not developing diabetes. Peripheral blood NK cell number was greater in poly I:C than in saline-treated rats, after 2 wk of treatment and when killed. The percentage of OX19+ peripheral blood mononuclear cells expressing RT6.1 allotype or Ia antigen were similar in poly I:C- and saline-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

“…Poly(I:C) was able to prevent diabetes in NOD (non-obese diabetic) mice 38 , but it was shown in diabetes-prone bio-breeding (DP-BB) rats that poly(I:C) can accelerate 39,40 or prevent diabetes, depending on the dosage used 41 . These contradictory observations may be partially explained by differences in doses and different kinetics of poly(I:C).…”

Role of Interferon Regulatory Factor-1 in Double-stranded RNA-induced iNOS Expression by Mouse Islets

“…dsRNA is an active component of a viral infection that stimulates host antiviral responses, including the production of cytokines and nitric oxide (17)(18)(19)(20). The synthetic dsRNA molecule poly(I-C) also activates the antiviral response (16) and has been shown to stimulate the development of diabetes in diabetesresistant BioBreeding rats and to accelerate disease development in diabetes-prone BioBreeding rats (21,22). We have shown that dsRNA, in combination with IFN-␥, induces islet dysfunction and destruction by a mechanism that is dependent on the expression of iNOS and production of nitric oxide by ␤ cells (23,24).…”

Toll-like Receptor 3 and STAT-1 Contribute to Double-stranded RNA+ Interferon-γ-induced Apoptosis in Primary Pancreatic β-Cells

“…These antiviral responses can be mimicked by the synthetic dsRNA polyinosinic-polycytidylic acid (PIC) (15,16). In vivo, PIC triggers the development of hyperglycemia in diabetes-resistant BioBreeding rats and accelerates the development of the disease in diabetes-prone BioBreeding rats (17,18). In vitro, PIC inhibits glucose-stimulated insulin biosynthesis in mouse islets (19) and, when used in combination with IFN-␥, decreases rat islet cell function and viability (11,20).…”