C protein-induced myocarditis and subsequent dilated cardiomyopathy: Rescue from death and prevention of dilated cardiomyopathy by chemokine receptor DNA therapy
C protein-induced myocarditis and subsequent dilated cardiomyopathy: Rescue from death and prevention of dilated cardiomyopathy by chemokine receptor DNA therapy
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DOI：
10.4049/jimmunol.173.5.3535
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发表时间：
2004-09-01
影响因子：
4.4
通讯作者：
Kohyama, K
中科院分区：
文献类型：
--
作者：
Matsumoto, Y;Tsukada, Y;Kohyama, K
用重组心肌C蛋白免疫Lewis大鼠，成功地复制了重症实验性自身免疫性心肌炎和随后的扩张型心肌病(DCM)。免疫后15天至49天，75%的免疫大鼠死亡，所有存活的大鼠都表现出典型的扩张性心肌病，其特征是存在脑室扩张和广泛的纤维化。急性期免疫病理和趋化因子分析显示，心肌细胞明显坏死，巨噬细胞浸润，单核细胞趋化蛋白-1和干扰素-γ诱导蛋白-10表达上调。基于这些发现，我们制备了编码CCR2和CXCR3结合位点的质粒DNA，这两个受体分别是MCP-1和IP-10的受体。细胞培养上清对MCP-1和IP-10诱导的T细胞和巨噬细胞的迁移有抑制作用。值得注意的是，给C蛋白免疫的大鼠注射DNA可以阻止疾病的发展，并将动物从死亡中拯救出来。本研究首次证明，针对趋化因子受体的基因治疗可能是控制实验性自身免疫性心肌炎和扩张性心肌炎的有力工具。
Severe experimental autoimmune myocarditis and subsequent dilated cardiomyopathy (DCM) were successfully produced in Lewis rats by immunization with recombinant cardiac C protein. Seventy-five percent of immunized rats died between days 15 and 49 postimmunization, and all of the survived rats showed typical DCM characterized by the presence of ventricular dilatation and extensive fibrosis. Immunopathological and chemokine analysis during the acute phase revealed that there were marked macrophage infiltration with myocyte necrosis and up-regulation of MCP-1 and IFN-gamma-inducible protein-10 (IP-10). Based on these findings, we prepared plasmid DNAs encoding the binding site of CCR2 and CXCR3, which are receptors for MCP-1 and IP-10, respectively. The culture supernatant of cells transfected with these DNAs inhibited the migration of T cells and macrophages induced by MCP-1 and IP-10. Remarkably, administration of the DNAs to C protein-immunized rats prevented the disease progression and rescued animals from death. The present study has demonstrated for the first time that gene therapy targeting the chemokine receptor could be a powerful tool for the control of experimental autoimmune myocarditis and DCM.