A study of molecular diagnosis and treatment for chronic cardiac allograft rejection.

慢性心脏同种异体移植排斥反应的分子诊断和治疗研究。

• 批准号: 10557122
• 负责人: SHIRAKURA Ryota
• 金额: $ 7.68万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 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/en/grant/KAKENHI-PROJECT-10557122/
• 关键词: Chronic rejection; Rat; Heterotopic heart transplantation; Quantitative RT-PCR; 定量的RT-PCR法

This study was performed as three parts described as below.1 : We have measured the dynamics of 65 different immune gene expressions using real-time quantitative RT-PCR in retransplanted rat hearts developing cardiac allograft vasculopathy (CAV). This retransplantation model provided better opportunities to investigate the molecular mechanism, because the correlation between the occurrence of chronic rejection and the expression pattern of the identified gene was more stringent than those in other animal models. In summary of this part of the study, the importance of selective chemokine/receptor systems including IP10-CXCR3, RANTES-CCR5, and MCP1-CCR2 was indicated in addition to the implication of cytokines produced by activated T cells (IFN-γ and Fas ligand), growth factors for vascular smooth muscle cells (PDGF-β, TGF-β) in the progression of CAV.2 : The developed technology using real-time RT-PCR was applied to the investigation of Myasthenia Gravis in clinical situation and provid … More ed the data suggesting the implication of suppressed class II transactivator gene-expression of dysregulation of MHC class II antigen on thymoma cells in pathogenesis of the disease. This results also indicated the feasibility of this method in clinical diagnosis of various diseases includeing CAV.3 : Experimental gene therapy was performed using beta-adrenergic receptor gene and hepatocyte growth factor gene. In both cases, ischemia-reperfusion injury was attenuated by the introduction of either gene into a whole heart in vivo. It is conceivable that the technique should provide the way to treat CAV in clinical situation, because CAV is a local disorder under systemic immunosuppression.Clinical heart transplantation in Japan has just began and it was impossible to apply the technique developed in this study on the clinical diagnosis of chronic rejection as originally planed. Nonetheless, this study provided several new methods applicable to the diagnosis and the treatment of CAV in clinical situation. Less

本研究分三部分进行：1.采用实时荧光定量RT-PCR技术检测了大鼠心脏移植后移植心脏血管病变（cardiac allograft vasculopathy，CAV）中65种不同免疫基因表达的动态变化。这种再移植模型提供了更好的机会来研究分子机制，因为慢性排斥反应的发生与所鉴定基因的表达模式之间的相关性比其他动物模型中的那些更严格。总结这部分研究，除了活化T细胞产生的细胞因子外，还指出了选择性趋化因子/受体系统包括IP 10-CXCR 3、RANTES-CCR 5和MCP 1-CCR 2的重要性（IFN-γ和Fas配体），血管平滑肌细胞生长因子2、实时荧光定量RT-PCR技术应用于重症肌无力的临床研究，为临床诊断重症肌无力提供了一种新的方法。 ...更多信息 艾德的数据表明，抑制II类反式激活因子基因表达的异常调节的MHC II类抗原的胸腺瘤细胞在疾病的发病机制的影响。这一结果也表明了该方法在临床诊断包括CAV在内的各种疾病中的可行性。3：使用β-肾上腺素能受体基因和肝细胞生长因子基因进行实验性基因治疗。在这两种情况下，缺血-再灌注损伤减弱的基因导入到体内的整个心脏。由于CAV是一种全身免疫抑制下的局部疾病，因此可以想象，该技术将为临床治疗CAV提供一种方法，日本的临床心脏移植才刚刚开始，不可能按原计划将本研究开发的技术应用于慢性排斥反应的临床诊断。本研究为临床诊断和治疗CAV提供了新的方法。少

项目成果

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