Gene therapy with CCL2 (MCP-1) mutant protects CVB3-induced myocarditis by compromising Th1 polarization
Gene therapy with CCL2 (MCP-1) mutant protects CVB3-induced myocarditis by compromising Th1 polarization
复制标题
CCL2 (MCP-1) 突变体基因治疗通过损害 Th1 极化来保护 CVB3 诱导的心肌炎
DOI：
10.1016/j.molimm.2010.11.018
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Yue, Yan;Gui, Jun;Xiong, Sidong
病毒性心肌炎最常见由柯萨奇病毒B3（CVB3）感染引起，影响着全球约5 - 20%的人口，且缺乏有效的治疗方法。我们先前报道过，在CVB3感染期间单核细胞趋化蛋白 - 1（MCP - 1，CCL2）会被显著诱导，并对心肌炎症和损伤有很大影响。在此，我们使用了一种趋化活性被去除的CCL2突变体，并探究了其对CVB3诱导的心肌炎的治疗效果。构建了一种显性失活的CCL2突变体，其缺失了N端的2 - 8位氨基酸（CCL2（Δ2 - 8）），在CVB3感染后将其肌肉注射到BALB/c小鼠体内，通过体重减轻、存活率、血清学指标和病理观察来评估心肌炎的严重程度。还评估了全身性和局部的Th1/Th2细胞因子谱。与pcDNA3.1组或未处理组小鼠相比，接受pCCL2（Δ2 - 8）的小鼠心肌炎明显减轻，表现为体重稳定、血清肌酸激酶同工酶（CK - MB）水平降低、心肌炎症浸润减少以及存活率提高。这种效果并非归因于有效的病毒清除，而是与Th1免疫反应减弱有关，这体现在全身性和局部的CD4⁺IFN - γ⁺ T细胞频率以及Th1细胞因子水平显著降低。体内阻断CCL2活性的策略可有效减轻CVB3诱导的心肌炎的严重程度，并可能为病毒性心肌炎提供一种替代的治疗方法。（C）2010爱思唯尔有限公司。保留所有权利。
Viral myocarditis, which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, affects about 5-20% of the world population and lacks efficient treatments. We previously reported that monocyte chemotactic protein-1 (MCP-1, CCL2) was significantly induced during CVB3 infection and greatly contributed to the myocardic inflammation and injury. Herein a CCL2 mutant with removed chemotactic activity was administrated and its therapeutic effect on CVB3-induced myocarditis was explored. A dominant negative CCL2 mutant, lacking the N-terminal amino acids 2-8 (CCL2(Delta 2-8)), was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection, severity of myocarditis was evaluated by weight loss, survival rate, serological indices and pathological observation. Systemic and local Th1 /Th2 cytokine profiles were also assessed. Mice receiving pCCL2(Delta 2-8) exhibited a profound attenuation of myocarditis compared to pcDNA3.1 or non-treated mice, as evidenced by invariant body weight, decreased serum CK-MB level, reduced myocardial inflammatory infiltration and increased survival. This effect was not attributable to the efficient viral clearance, but associated with weakened Th1 immune responses, as evidenced by significantly reduced CD4(+)IFN-gamma(+) T cell frequency and Th1 cytokine level systemically and locally. Strategy of blocking in vivo CCL2 activity could effectively alleviate the severity of CVB3-induced myocarditis and may present an alternative therapeutic approach against viral myocarditis. (C) 2010 Elsevier Ltd. All rights reserved.