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

心脏肌球蛋白诱导的大鼠实验性自身免疫性心肌炎（EAM）是人类巨细胞心肌炎的动物模型。在急性暴发阶段后，EAM导致心肌病后的心肌病扩张。使用EAM研究了自身免疫性心肌损伤的发病机理。在本质上，我们分析了心肌浸润的T细胞的T细胞受体完整性确定3（CDR3）的结构。当大鼠用心脏肌球蛋白棒蛋白免疫时，限制了心脏浸润的T细胞的CDR3基序。心脏肌球蛋白棒蛋白包含多个心肌源性表位。当通过合成心肌生成肽的免疫抑制诱导EAM时，心脏浸润的T细胞是寡聚的。病变中T细胞的CDR4基序的分析可能是自身免疫发病机理的标志物（循环研究83：133-140，1998）。细胞因子在自身免疫性心肌损伤的发病机理中起重要作用。 IL-12将Th0 T细胞促进具有…更多Th1功能的T细胞。 IL-12的信使RNA在EAM的心肌中表达。研究了IL-12的效应。 IL-12的体内给药将EMA的自然过程转移到了严重和持续的形式。这是与EAM（循环）研究的发作，进展和持久性有关的Th1极性82：1035-1042，1998）。最近发现了Coxsakievivirus和腺病毒受体（CAR），其基因已被克隆。该分子可能与心肌炎的敏感性有关。我们研究了在新生儿心肌上表达CAR的CAR在大鼠心脏中的表达，但在成年大鼠心脏上无法检测到它。在EAM过程中，自免疫后18天从心肌上表达了汽车的mRNA。免疫组织化学还揭示了汽车在第24天的心肌上的表达。体外研究表明，炎症细胞因子诱导了汽车的心肌表达（循环研究86：275-280，2000）。心肌炎的临床表现从不对称到暴发和致命形式不等。尚未确定疾病病程的预测因素。我们检查了急性心肌炎患者疾病病程中各种参数的预测值。我们在尼加塔县收集了人类心肌炎病例。分析了21名保守性组织学性心肌炎的保守患者。 13名患者可以在急性期生存并保留。与生存组相比，该致命组的血压较低和较高的肺毛细血管楔压。致命组的固体FAS和FAS配体的血清水平明显高于生存组。可溶性FAS和FAS配体将是预测心肌炎患者预后的血清学标记（循环102：2829-2835，2000）。较少的

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)。

Kenichi Watanabe, Yoshimi Ohta, Takahiro Kouda, Tomoyuki Sekiguchi, Shinji Sato, Mikio Nakazawa, Go Hasegawa, Makoto Naito, Koichi Fuse, Masahiro Ito, Satoru Hirono, Naihito Tanabe, Haruo Hanawa, Kiminori Kato, Makoto Kodama, Yoshifusa Aizawa.: "Acute eff

渡边健一、太田佳美、幸田贵宏、关口智之、佐藤真司、中泽干夫、长谷川豪、内藤诚、布施浩一、伊藤雅宏、广野悟、田边内仁、花轮春夫、加藤公纪、小玉诚、相泽良房。：

Watanabe K,Kodama M: "Effects of long -term treatment with carvedilol in rats with dilated cardiomyopathy after myocarditis"Journal of Cardiovascular Pharmacology. 34(suppl 4). S77-S80 (1999)

Watanabe K，Kodama M：“卡维地洛长期治疗对心肌炎后扩张型心肌病大鼠的影响”心血管药理学杂志。

Haruo Hanawa, Tohru Izumi, Yuji Saito, Yukie Ochiai, Yuji Okura, Takayuki Inomata, Satoru Hirono, Yusuke Ogawa, Reiko Saito, Makoto Kodama, Norio Higuma, Yoshifusa Aizawa: "Recovery from complete atrioventricular block caused by idiopathic giant cell myoc

Haruo Hanawa、Tohru Izumi、Yuji Saito、Yukie Ochiai、Yuji Okura、Takayuki Inomata、Satoru Hirono、Yusuke Okawa、Reiko Saito、Makoto Kodama、Norio Higuma、Yoshifusa Aizawa：“从特发性巨细胞肌病引起的完全房室传导阻滞中恢复