Direct Gene Transfer with IP-10 Mutant Ameliorates Mouse CVB3-Induced Myocarditis by Blunting Th1 Immune Responses
Direct Gene Transfer with IP-10 Mutant Ameliorates Mouse CVB3-Induced Myocarditis by Blunting Th1 Immune Responses
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IP-10 突变体直接基因转移通过减弱 Th1 免疫反应改善小鼠 CVB3 诱导的心肌炎
DOI：
10.1371/journal.pone.0018186
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发表时间：
2011-03-22
期刊：
影响因子：
3.7
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Yue, Yan;Gui, Jun;Xiong, Sidong
背景：心肌炎是心肌的一种炎症，通常继发于肠道病毒感染，柯萨奇病毒B3（CVB3）是最主要的病原体。我们及其他研究小组先前报道，趋化因子IP - 10在CVB3感染小鼠的心脏组织中显著诱导产生，并促使大量炎症细胞迁移至心肌，这是病毒性心肌炎最重要的机制之一。为了评估IP - 10对CVB3心肌炎炎症反应的直接作用，在此我们将一种缺失趋化吸引功能的IP - 10突变体引入小鼠体内以拮抗内源性IP - 10的活性，并评估其对CVB3诱导的心肌炎的治疗效果。
方法/主要发现：通过基因工程构建了缺失突变体pIP - 10 - AT，即在去除5个N端氨基酸后添加了一个甲硫氨酸，并在CVB3感染后将其肌肉注射到BALB/c小鼠体内。与载体组或未治疗组相比，pIP - 10 - AT治疗显著降低了心脏/体重比和血清肌酸激酶同工酶（CK - MB）水平，提高了存活率并改善了心脏组织病理学，表明心肌炎得到缓解。这种治疗效果并非归因于病毒清除增强，而是由于Th1免疫反应减弱，这可由脾脏CD4(+) / CD8(+)干扰素 - γ(+) T细胞百分比显著降低以及心肌Th1细胞因子水平降低所证明。
结论/意义：我们的研究结果构成了首个临床前数据，表明体内干扰IP - 10活性可缓解CVB3诱导的心肌炎。这一策略可能代表了一种治疗病毒性心肌炎的新治疗方法。
Background Myocarditis is an inflammation of the myocardium that often follows the enterovirus infections, with coxsackievirus B3 (CVB3) being the most dominant etiologic agent. We and other groups previously reported that chemokine IP-10 was significantly induced in the heart tissue of CVB3-infected mice and contributed to the migration of massive inflammatory cells into the myocardium, which represents one of the most important mechanisms of viral myocarditis. To evaluate the direct effect of IP-10 on the inflammatory responses in CVB3 myocarditis, herein an IP-10 mutant deprived of chemo-attractant function was introduced into mice to antagonize the endogenous IP-10 activity, and its therapeutic effect on CVB3-induced myocarditis was evaluated. Methodology/Principal Findings The depletion mutant pIP-10-AT, with an additional methionine after removal of the 5 N-terminal amino acids, was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection. Compared with vector or no treatment, pIP-10-AT treatment had significantly reduced heart/body weight ratio and serum CK-MB level, increased survival rate and improved heart histopathology, suggesting an ameliorated myocarditis. This therapeutic effect was not attributable to an enhanced viral clearance, but to a blunted Th1 immune response, as evidenced by significantly decreased splenic CD4+/CD8+IFN-γ+ T cell percentages and reduced myocardial Th1 cytokine levels. Conclusion/Significance Our findings constitute the first preclinical data indicating that interfering in vivo IP-10 activity could ameliorate CVB3 induced myocarditis. This strategy may represent as a new therapeutic approach in treating viral myocarditis.