Sobel D O, Goyal D, Ahvazi B, Yoon J W, Chung Y H, Bagg A, Harlan D M
Georgetown University School of Medicine, Washington, DC 20007, USA.
J Autoimmun. 1998 Aug;11(4):343-52. doi: 10.1006/jaut.1998.0203.
Poly I:C, an inducer of IFN-alpha and other cytokines, has been used to study the development of diabetes in both the BioBreeding (BB) diabetes prone rat and non-obese diabetic (NOD) mouse animal models of insulin-dependent diabetes mellitus (IDDM). Surprisingly, poly I:C accelerates the disease in the BB rat while inhibiting it in the NOD mouse. Since cytokines can have dose related opposing effects on immune responses, we hypothesized that the paradoxical effect of polyinosinic polycytidylic 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 microg/g body weight and 0.1 microg/g body weight) up to 100-fold lower than doses (poly-5 microg/g) previously found to accelerate diabetes. In addition, the non-specific suppressor activity of mononuclear splenocytes from BB rats administered low dose (poly-0.05 microg/g body weight), high dose (poly-5 microg/g body weight), and saline were 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 treated animals was also less severe. The total white blood cell count and proportion of RT6+ T-cells and each T-cell subset were unaltered by poly I:C. When compared to splenocytes of control animals, splenocytes from poly I:C (0.05 microg/g body weight) treated rats suppressed responder cell proliferation to concanavalin A and alloantigen. However, spleen cells from high dose poly-I:C did not suppress responder cell proliferation to alloantigen. In adoptive transfer studies, the administration of spleen cells from poly-0.05 treated rats decreased the development of diabetes in recipient BB rats. In vitro studies also demonstrated that poly-I:C inhibits the proliferative response of BB rat spleen cells to concanavalin A. The administration of poly-0.05, but not poly-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 required 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 the inhibition of T-cell responses by poly-I:C in vitro suggests that the diabetes sparing activity of poly I:C is mediated by augmented immunoregulatory cell activity. Further studies with poly I:C may be important in increasing our understanding of the pathogenesis of IDDM and provide a means to prevent it.
聚肌胞苷酸（Poly I:C）是一种干扰素-α及其他细胞因子的诱导剂，已被用于研究生物繁殖（BB）糖尿病易患大鼠和非肥胖糖尿病（NOD）小鼠这两种胰岛素依赖型糖尿病（IDDM）动物模型中糖尿病的发展情况。令人惊讶的是，聚肌胞苷酸在BB大鼠中加速了疾病进程，而在NOD小鼠中却抑制了疾病发展。由于细胞因子对免疫反应可能有与剂量相关的相反作用，我们推测聚肌苷酸-聚胞苷酸（Poly I:C）在这两种动物模型中对糖尿病产生的矛盾效应与剂量有关。因此，我们比较了给予生理盐水和不同剂量聚肌胞苷酸（0.05微克/克体重和0.1微克/克体重，比先前发现可加速糖尿病的剂量（聚-5微克/克）低至100倍）的糖尿病易患BB大鼠的糖尿病发病率和胰岛炎程度。此外，还比较了给予低剂量（聚-0.05微克/克体重）、高剂量（聚-5微克/克体重）聚肌胞苷酸和生理盐水的BB大鼠脾单核细胞的非特异性抑制活性。各剂量聚肌胞苷酸处理的大鼠糖尿病发展均受到抑制。聚肌胞苷酸处理动物的胰岛炎程度也较轻。聚肌胞苷酸未改变白细胞总数、RT6 + T细胞及各T细胞亚群的比例。与对照动物的脾细胞相比，聚肌胞苷酸（0.05微克/克体重）处理大鼠的脾细胞抑制了应答细胞对刀豆蛋白A和同种异体抗原的增殖。然而，高剂量聚肌胞苷酸处理的脾细胞未抑制应答细胞对同种异体抗原的增殖。在过继转移研究中，给予聚-0.05处理大鼠的脾细胞可降低受体BB大鼠糖尿病的发展。体外研究还表明，聚肌胞苷酸抑制BB大鼠脾细胞对刀豆蛋白A的增殖反应。给予聚-0.05而非聚-5.0可降低脾细胞中肿瘤坏死因子-α mRNA和白细胞介素-10 mRNA的含量。我们得出结论，聚肌胞苷酸以比加速糖尿病所需剂量低100倍的剂量，通过干扰胰岛炎的发展，预防了BB大鼠糖尿病的发生。低剂量聚肌胞苷酸在体内诱导抑制细胞活性以及聚肌胞苷酸在体外抑制T细胞反应表明，聚肌胞苷酸对糖尿病的预防作用是由增强的免疫调节细胞活性介导的。对聚肌胞苷酸的进一步研究可能对增进我们对IDDM发病机制的理解很重要，并提供一种预防方法。
