Prevention of experimental autoimmune myocarditis by hydrodynamics-based naked plasmid DNA encoding CTLA4-Ig gene delivery
Prevention of experimental autoimmune myocarditis by hydrodynamics-based naked plasmid DNA encoding CTLA4-Ig gene delivery
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DOI：
10.1016/j.cardfail.2005.04.005
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发表时间：
2005-09-01
影响因子：
6
通讯作者：
Aizawa, Y
中科院分区：
文献类型：
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作者：
Abe, S;Hanawa, M;Aizawa, Y
背景：大鼠实验性自身免疫性心肌炎（EAM）是一种T细胞介导的疾病，类似于人类巨细胞心肌炎。可溶性CTLA4通过阻断T细胞共刺激信号改善某些自身免疫性疾病。我们研究了基于流体动力学的裸质粒DNA编码ctla4免疫球蛋白（Ig）基因传递的效果。方法与结果：采用心肌肌球蛋白免疫Lewis大鼠，第0天采用流体动力学转染，即尾静脉快速注射大量编码CTLA4-Ig嵌合液的pCAGGS。载体衍生的CTLA4-Ig mRNA主要在肝脏表达，实验期间血浆CTLA4-Ig蛋白水平维持在2 μ g/mL左右。第17天，CTLA4组大鼠心重比、房利钠肽mRNA表达量、炎症面积均显著低于空质粒对照组。CTLA4-Ig治疗后，最大室内压上升和下降率（dP/dT）、最小dP/dT、左室舒张末期压和中心静脉压均有显著改善。第14天，CTLA4-Ig组腘窝淋巴结IL-2表达明显低于对照组。结论：以水动力学方法转染编码CTLA4-Ig嵌合体的质粒可显著预防EAM。
Background: Rat experimental autoimmune myocarditis (EAM) is a T cell-mediated disease that resembled the giant cell myocarditis seen in humans. Soluble CTLA4 improves some autoimmune diseases by blocking costimulatory signals on T cell. We investigated the effect of hydrodynamics-based naked plasmid DNA encoding CTLA4-immunoglobulin (Ig) gene delivery.Methods and Results: Lewis rats were immunized with cardiac myosin and treated with hydrodynamic-based transfection, namely a rapid tail vein injection of a large volume of pCAGGS encoding CTLA4-Ig chimera solution on Day 0. The vector-derived CTLA4-Ig mRNA expressions were mainly detected in the liver and plasma CTLA4-Ig protein levels were maintained at about 2 mu g/mL during the experiment period. On Day 17, the ratio of heart to body weight, the amount of mRNA of atrial natriuretic peptide, and the inflammatory areas in CTLA4 group were significantly lower than in the control group treated with empty plasmid. Maximum rate of intraventricular pressure rise and decline (dP/dT), minimum dP/dT, left ventricular end-diastolic pressure, and central venous pressure improved significantly after treatment with CTLA4-Ig. On Day 14, expressions of IL-2 in popliteal lymph nodes in the CTLA4-Ig group were significantly lower than in the control group.Conclusion: Hydrodynamics-based transfection of plasmid encoding CTLA4-Ig chimera dramatically prevented EAM.