Qin H Y, Elliott J F, Lakey J R, Rajotte R V, Singh B
Department of Microbiology and Immunology, University of Western Ontario, Canada.
J Autoimmun. 1998 Dec;11(6):591-601. doi: 10.1006/jaut.1998.0243.
We have shown that immunization of non-obese diabetic (NOD) mice with adjuvants (CFA or BCG) prevents the onset of diabetes by induction of regulatory cells. Since autoimmune responses to glutamic acid decarboxylase (GAD) are up-regulated in insulin-dependent diabetes mellitus (IDDM), in this study GAD67-specific antibody, T cell proliferation and lymphokine production patterns were analysed in the adjuvant-treated mice to characterize the regulatory mechanisms underlying the protection. We used both spontaneous diabetes and syngeneic islet transplantation models in NOD mice. Protection against spontaneous diabetes and prevention of syngeneic islet graft rejection by CFA or BCG treatment was found to be accompanied by the production of long lasting and high titre anti-GAD67 antibody of IgG1 isotype in the sera. Upon in vitro stimulation with GAD67, draining lymph node and spleen cells from CFA-immunized NOD mice or syngeneic islet-grafted and BCG-protected NOD mice produced much more IL-4, whereas there was no significant change in IFN-gamma production. The strong early T cell proliferative response to GAD67 in CFA or BCG-immunized NOD mice was followed by a low or unresponsiveness state. Taken together, these results suggest a shift in Th1/Th2 balance in the GAD67-specific endogenous immune response to a change in Th2 levels after adjuvant treatment. We postulate that the protective effect of CFA or BCG is due to the diversion of GAD-specific endogenous cellular immune response to a non-pathogenic humoral response.
我们已经表明，用佐剂（完全弗氏佐剂或卡介苗）免疫非肥胖糖尿病（NOD）小鼠可通过诱导调节性细胞来预防糖尿病的发生。由于在胰岛素依赖型糖尿病（IDDM）中，对谷氨酸脱羧酶（GAD）的自身免疫反应上调，因此在本研究中，对经佐剂处理的小鼠分析了GAD67特异性抗体、T细胞增殖和淋巴因子产生模式，以表征保护作用背后的调节机制。我们在NOD小鼠中使用了自发性糖尿病和同基因胰岛移植模型。发现用完全弗氏佐剂或卡介苗处理可预防自发性糖尿病并防止同基因胰岛移植排斥，同时血清中会产生持久且高滴度的IgG1同种型抗GAD67抗体。用GAD67进行体外刺激后，来自经完全弗氏佐剂免疫的NOD小鼠或同基因胰岛移植且经卡介苗保护的NOD小鼠的引流淋巴结和脾细胞产生的白细胞介素-4要多得多，而干扰素-γ的产生没有显著变化。在经完全弗氏佐剂或卡介苗免疫的NOD小鼠中，T细胞对GAD67的早期强烈增殖反应之后是低反应或无反应状态。综上所述，这些结果表明，在佐剂处理后，GAD67特异性内源性免疫反应中的Th1/Th2平衡向Th2水平的变化发生了转变。我们推测，完全弗氏佐剂或卡介苗的保护作用是由于GAD特异性内源性细胞免疫反应转向了非致病性体液反应。
