Development of the Specific Immunotherapy for Myocarditis, Dilated Cardiomyopathy(Chronic Myocarditis), and Takayasu Arteritis.

1.心肌炎和扩张型心肌病心脏浸润性细胞T细胞受体克隆性分析：SSCP显示TCRVβ克隆性为寡克隆性，约40%的克隆在同一心脏不同部位之间一致，约40%的克隆同时在外周血中扩增。这表明有可能从外周血中收集致病T细胞克隆识别的抗原，这些克隆在疾病的发展中起主要作用。2.共刺激分子在急性和慢性心肌炎T细胞介导的心肌损伤中起重要作用的分析：(A)对急性心肌炎小鼠的肿瘤坏死因子受体/配体超家族共刺激分子进行了分析，发现心肌细胞上可诱导CD30L、4-1BBL、Fas，体内给予抗4-1BBL或-FasL单抗可显著减轻心肌损伤，提示4-1BB/4-1BBL和Fa…在心肌损伤中起关键作用。更多涉及S/FasL通路。(2)我们发现在急性心肌炎和扩张性心肌炎患者心肌细胞上CD27L、CD30L、OX40L和4-1BBL的表达及其相应分子的表达，提示这些共刺激分子在人类心肌炎的发病机制中也起着作用。3.Takayasu大动脉炎动脉浸润性细胞TcR克隆性分析：(1)单链构象分析显示TCRVβ克隆性为寡克隆性，同一动脉组织内不同部位的TCRV克隆多数相同，提示有少量克隆体侵入并识别某种抗原，造成血管损伤。(2)与TcRγδ一样，浸润性细胞的TcRαβ谱系均为寡克隆。4.大动脉炎共刺激分子的分析：在肿瘤坏死因子受体/配体超家族共刺激分子中，特别是4-1BB/4-1BBL和Fas/FasL通路在大动脉炎的血管损伤中起重要作用。较少

1. Analysis of T-cell receptor(TCR)clonality of the heart infiltrating cells in myocarditis and dilated cardiomyopathy(DCM) : SSCP showed that TCR Vβ clonality was oligoclonal and about 40% of the total clones were identical among different three parts in the same heart and that about 40% of such clones also expanded in the peripheral blood. This indicates a possibility of identification of the antigen recognized by pathogenic T-cell clones playing a primary role in the development of the disease by collecting them from peripheral blood. 2. Analysis of costimulatory molecules playing an important role in the T-cell-mediated myocardial damage in acute and chronic myocarditis : (A)We analyzed TNF receptor/ligand superfamily costimulatory molecules in murine acute myocarditis, and found that CD30L, 4-1BBL, Fas were induced on cardiac myocytes and in vivo anti-4-1BBL or -FasL mAb administration significantly reduced the myocardial damage, indicating the critical role of 4-1BB/4-1BBL and Fa … More s/FasL pathways involved. (B)We found the induction of CD27L, CD30L, OX40L, and 4-1BBL on cardiac myocytes and expression of their counterpart by the infiltrating cells in patients with acute myocarditis and DCM, suggesting the role of these costimulatory molecules in the pathogenesis is of human myocarditis as well. 3. Analysis of TCR clonality of the arterial infiltrating cells in Takayasu Arteritis : (A)SSCP showed that TCR Vβ clonality was oligoclonal and most of the clones were identical between different two parts in the same arterial tissue, suggesting that limited clones infiltrated and recognized a certain antigen and caused vascular damage. (B)TCR γδ repertoire of the infiltrating cells was oligoclonal as was TCR αβ. 4. Analysis of costimulatory molecules in Takayasu Arteritis : It is strongly suggested that among TNF receptor/ligand superfamily costimulatory molecules, especially 4-1BB/4-1BBL and Fas/FasL pathways play an important role in the vascular damage involved in Takayasu Arteritis. Less