Qin H Y, Singh B
Department of Microbiology and Immunology, University of Western Ontario and John P. Robarts Research Institute, London, Canada.
J Autoimmun. 1997 Jun;10(3):271-8. doi: 10.1006/jaut.1997.0136.
We have previously shown that immunotherapy with complete Freund's adjuvant (CFA) or BCG is highly effective in the prevention of spontaneous insulin-dependent diabetes mellitus (IDDM) and in circumventing the rejection of syngeneic islet grafts in diabetic NOD mice. This protection is reversed by treatment with cyclophosphamide (Cy). The present study was undertaken to determine the effect of BCG vaccination on the progression of Cy-accelerated diabetes in NOD mice and to understand the mechanism of BCG immunotherapy. The time course of Cy and BCG administration showed that the progression of Cy-induced diabetes can only be blocked when BCG vaccination is given within 3 days of Cy administration. Mice given BCG 3 days before (-3 days) or 7 days after Cy treatment were not protected. BCG immunization 1 day after Cy treatment almost completely prevented insulitis in the islets of Cy-treated mice. Cy treatment reduced the endogenous production of anti-GAD67 antibody, whereas BCG vaccination 1 day after Cy treatment restored the production of anti-GAD67 antibody of IgG1 isotype. The comprehensive effect of BCG vaccination on cytokine production in Cy-treated mice was to increase IL-4 production and change the IL-4/IFN-gamma ratio in both serum and supernatant of spleen cell cultures. We found that BCG-induced protection was associated with increased splenic CD4+CD45 RB(high) T cells. Taken together, our results indicate that BCG treatment counteracts the effect of Cy on autoimmune process in IDDM. However, BCG immunotherapy has a narrow window of up to 3 days after Cy treatment to block the progression of Cy-induced diabetes and to allow for the induction of regulatory cells which may effectively downregulate the diabetogenic cells. In summary, our results suggest that BCG vaccination prevents IDDM if given in the prediabetic state. After the induction of diabetes, disease progression can only be prevented within a narrow window of opportunity by this treatment.
我们之前已经表明，用完全弗氏佐剂（CFA）或卡介苗进行免疫治疗在预防自发性胰岛素依赖型糖尿病（IDDM）以及规避糖尿病NOD小鼠中同基因胰岛移植的排斥方面非常有效。这种保护作用可被环磷酰胺（Cy）治疗逆转。本研究旨在确定卡介苗接种对NOD小鼠中Cy加速糖尿病进展的影响，并了解卡介苗免疫治疗的机制。Cy和卡介苗给药的时间进程表明，只有在Cy给药后3天内进行卡介苗接种，才能阻断Cy诱导的糖尿病进展。在Cy治疗前3天（-3天）或后7天给予卡介苗的小鼠未得到保护。Cy治疗后1天进行卡介苗免疫几乎完全预防了Cy治疗小鼠胰岛中的胰岛炎。Cy治疗降低了抗GAD67抗体的内源性产生，而Cy治疗后1天进行卡介苗接种恢复了IgG1同种型抗GAD67抗体的产生。卡介苗接种对Cy治疗小鼠细胞因子产生的综合作用是增加IL-4的产生，并改变脾细胞培养上清液和血清中的IL-4/IFN-γ比值。我们发现卡介苗诱导的保护作用与脾脏CD4+CD45 RB(high) T细胞增加有关。综上所述，我们的结果表明，卡介苗治疗可抵消Cy对IDDM自身免疫过程的影响。然而，卡介苗免疫治疗在Cy治疗后最多3天的狭窄窗口期内才能阻断Cy诱导的糖尿病进展，并允许诱导可有效下调致糖尿病细胞的调节性细胞。总之，我们的结果表明，如果在糖尿病前期状态下给予卡介苗接种可预防IDDM。在糖尿病诱导后，这种治疗只能在狭窄的机会窗口内预防疾病进展。
