抗CD4单抗诱导免疫耐受防治自身免疫性心肌炎的研究

Monodonal anti-CD4 prevents the development of experimental autoimmune myocarditis by inducing immune tolerance to cardiac myosin

目的探讨体内注射CD4单克隆抗体诱导大鼠对猪心肌肌凝蛋白产生免疫耐受及这种免疫耐受对自身免疫性心肌炎大鼠的治疗作用。方法分别于第0、7天给予Lewis大鼠体内注射猪心肌肌凝蛋白诱导自身免疫性心肌炎的产生。分别于第-2、-1、0、1天注射CD4单克隆抗体诱导免疫耐受。初次免疫后18d，检测免疫耐受的诱导情况及其对心肌炎大鼠的作用。结果同非治疗组鼠相比较，抗体治疗组鼠心功能明显改善；没有明显的心肌变性、坏死、炎症细胞浸润及纤维化；抗原特异性淋巴细胞增殖反应明显下降；血清抗心肌肌凝蛋白自身抗体明显降低；血清TH1细胞因子IFN-γ、IL-2的水平显著下调；TH2细胞因子IL-6、IL-10的水平没有改变或者被上调。结论CD4单抗能够诱导机体对猪心肌肌凝蛋白产生免疫耐受，通过免疫耐受的诱导阻止了自身免疫性心肌炎大鼠心功能的紊乱和心肌的损伤。

Objective To investigate whether monoclonal anti-CD4 can induce immune tolerance to porcine cardiac myosin and whether the immune tolerance can protect rats with autoimmune myocarditis from cardiac dysfunction and myocardial injury. Methods Lewis rots were immunized with porcine cardiac myosin at days 0 and 7 to induce experimental autoimmune myocarditis. Immune tolerance was induced by injections of monoclonal anfi-CD4 at days -2, -1, 0 and 1. Eighteen days after the first immunization, cardiac function was evaluated using transthoracic echocardiography. Pathological changes of hearts were observed under light microscope. Lymphocyte proliferative response to cardiac myosin was detected in vitro by lymphocyte proliferation assay. Serum levels of anti-cardiac myosin autoantibedy, TH1 cytokines including interfemn-γ and interleukin-2 and TH2 cytokines including interleukin-6 and interleukin-10 were examined by enzyme-linked immunosorbent assay. Results Cardiac function of antibedy-treated rots was significantly increased compared with untreated rots. Pathological findings demonstrated that myocardial degeneration, necrosis, infiltration of inflammatory ceils and fibrosis were observed obviously in untreated group but not in antibody-treated group. Antigen special lymphocyte proliferation was significantly inhibited by antibody administration. Serological examination showed that rats immunized with cardiac myosin could produce high levels of anti-cardiac myosin, but the administration of monoclonal anti-CD4 significantly prevented the increase of the serum anti-cardiac myosin level. Serum levels of TH1 cytokines were significantly down-regulated by antibody administration, and the production of TH2 cytokines was up-regulated or unaffected. Conclusion The present study indicates that immune tolerance to porcine cardiac myosin can be induced by monoclonal anti-CD4 in v/vo, and accordingly cardiac dysfunction and myocardial injury can be prevented by induction of immune tolerance .