Analysis of T-cell receptor β-chain complementarity-determining region 3 motifs of infiltrating T cells in the inflammatory lesions from human myocarditis

人心肌炎炎症病变浸润T细胞T细胞受体β链互补决定区3基序分析

• 批准号: 10670636
• 负责人: KODAMA Makoto
• 金额: $ 1.09万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670636/
• 关键词: myocarditis; experimental autoimmune myocarditis; CD2; coxsakievirus adenovius receptor; natriuretic peptides; cytokine; Fas; Fas ligand; 予後規定因子; sFas; sFasL; IL-10; 心サルコイド-シス; CAR; carvedilol; 心筋炎; T細胞受容体; アポトーシス

Cardiac myosin-induced rat experimental autoimmune myocarditis (EAM) is an animal model of human giant cell myocarditis. After the acute fulminant phase, EAM leads to post-myocarditis dilated cardiomyopathy. Pathogenesis of autoimmune myocardial injuries was investigated using EAM.Initially, we analyzed structure of the T-cell receptor complementarity determining region 3 (CDR3) of T-cells infiltrating in myocardium. When rats were immunized with cardiac myosin rod protein, CDR3 motif of the heart infiltrating T-cells were restricted. Cardiac myosin rod protein contains several myocarditogenic epitopes. When EAM was induced by immunization with a synthetic myocarditogenic peptide, heart infiltrating T-cells were oligoclonal. Analysis of CDR4 motif of t-cells in the lesion may be a marker for autoimmune pathogenesis (Circulation Research 83 : 133-140, 1998). Cytokines play important roles in the pathogenesis of autoimmune myocardial injuries. IL-12 promotes Th0 T-cells into T-cells with … More Th1 function. Messenger RNA of IL-12 was expressed in the myocardium in EAM.Effects of IL-12 were investigated. In vivo administration of IL-12 shifted the natural course of EMA to severe and persistent form. Thus, Th1 polarity related to the onset, progression and persistence of EAM (Circulation Research 82 : 1035-1042, 1998). Coxsakievirus and adenovirus receptor (CAR) has recently been found and its gene has been cloned. This molecule may be related to susceptibility of myocarditis. We investigated expression of CAR in the rat hearts with EAM.CAR was expressed on the neonatal myocardium, but it could not be detected on the adult rat heart. During the course of EAM, mRNA of CAR was expressed on the myocardium from 18 days after immunization. Immunohistochemistry also revealed expression of CAR on the myocardium from day 24. In vitro studies demonstrated that myocardial expression of CAR was induced by inflammatory cytokines (Circulation Research 86 : 275-280, 2000).Clinical manifestation of myocarditis vary from asymptomatic to fulminant and fatal form. The predictors of the course of the disease in patients with myocarditis have not yet been established. We examined the predictive values of various parameters in the disease course of patients with acute myocarditis. We collected human cases of myocarditis in Niigata prefecture. Twenty-one consecutive patients with histology-proven myocarditis were analyzed. Thirteen patients could survive acute phase and remainder were died. The fatal group had lower blood pressure and higher pulmonary capillary wedge pressure compared with the survival group. Serum levels of soluble Fas and Fas ligand were significantly higher in the fatal group than the survival group. Soluble Fas and Fas ligand would be serological marker to predict prognosis in patients with myocarditis (Circulation 102 : 2829-2835, 2000). Less

心肌球蛋白诱导的大鼠实验性自身免疫性心肌炎（EAM）是人类巨细胞性心肌炎的动物模型。急性暴发性发作期后，EAM可导致心肌炎后扩张型心肌病。应用EAM研究自身免疫性心肌损伤的发病机制。首先，我们分析了t细胞浸润心肌的t细胞受体互补决定区3 （CDR3）的结构。用心肌肌球蛋白棒蛋白免疫大鼠后，心脏浸润t细胞的CDR3基序受到限制。心肌肌球蛋白棒蛋白含有几个致心肌表位。当用合成的致心肌肽免疫诱导EAM时，心脏浸润t细胞是寡克隆的。对病变t细胞CDR4基序的分析可能是自身免疫发病机制的标志（Circulation Research 83: 133-140, 1998）。细胞因子在自身免疫性心肌损伤的发病机制中起重要作用。IL-12促进Th0 t细胞转化为具有更多Th1功能的t细胞。IL-12信使RNA在EAM心肌中表达。研究了IL-12的作用。体内给药IL-12将EMA的自然过程转变为严重和持久的形式。因此，Th1极性与EAM的发生、发展和持续有关（环流研究，82:1035-1042,1998）。柯萨奇病毒和腺病毒受体（CAR）是最近发现的，其基因已被克隆。该分子可能与心肌炎易感性有关。我们用EAM研究了CAR在大鼠心脏中的表达。CAR在新生心肌中有表达，在成年大鼠心肌中无表达。在EAM过程中，免疫后18 d开始心肌中CAR mRNA的表达。免疫组织化学也显示了第24天心肌上CAR的表达。体外研究表明，心肌中CAR的表达可由炎症细胞因子诱导（Circulation Research 86: 275- 280,2000）。心肌炎的临床表现从无症状到暴发性和致命性不等。心肌炎患者病程的预测因素尚未确定。我们研究了各种参数对急性心肌炎患者病程的预测价值。我们在新泻县收集了人类心肌炎病例。对连续21例经组织学证实的心肌炎患者进行分析。急性期存活13例，其余死亡。与生存组相比，死亡组血压较低，肺毛细血管楔压较高。死亡组血清可溶性Fas和Fas配体水平明显高于生存组。可溶性Fas和Fas配体可作为预测心肌炎患者预后的血清学指标（Circulation 102: 2829- 2835,2000）。少

项目成果

小玉 誠: "実験的自己免疫性心筋炎の病態"心筋の構造と代謝. 21(1998). 81-87 (1999)

Makoto Kodama：“实验性自身免疫性心肌炎的病理学”心肌结构和代谢21（1998）81-87（1999）。

塙 晴雄、小玉 誠: "繰り返す自己免疫心筋炎"呼吸と循環. 46. 463-468 (1998)

Haruo Hanawa、Makoto Kodama：“复发性自身免疫性心肌炎”呼吸与循环 46. 463-468 (1998)。

Masahiro Ito,Makoto Kodama 他: "Expression od coxsackievirus and adenovirus receptor in hearts of rats with experimental autoimmune myocarditis."Circulation Research. 86. 275-280 (2000)

Masahiro Ito、Makoto Kodama 等人：“实验性自身免疫性心肌炎大鼠心脏中柯萨奇病毒和腺病毒受体的表达”。循环研究 86. 275-280 (2000)。

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