Efficient Attenuation of NK Cell-Mediated Liver Injury through Genetically Manipulating Multiple Immunogenes by Using a Liver-Directed Vector
Efficient Attenuation of NK Cell-Mediated Liver Injury through Genetically Manipulating Multiple Immunogenes by Using a Liver-Directed Vector
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通过使用肝脏定向载体对多种免疫基因进行基因操作，有效减轻 NK 细胞介导的肝损伤
DOI：
10.4049/jimmunol.1203129
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发表时间：
2013-05-01
影响因子：
4.4
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
--
作者：
Geng, Jianlin;Wang, Xuefu;Tian, Zhigang
腺病毒或腺病毒载体被报道以NK细胞依赖的方式诱导严重的肝脏炎症，这限制了其用于肝脏基因治疗的临床应用。我们试图开发一种有效的肝脏定向治疗方法，通过同时操纵多个免疫基因来控制肝脏NK细胞功能。基于我们先前的研究，我们发现CCL 5敲低协同增强了腺病毒诱导的急性肝损伤中沉默CX 3CL 1（fractalkine [FKN]）的减弱作用。此外，人IL-10表达与FKN敲低的组合处理将进一步加强沉默FKN的保护作用。我们利用肝细胞特异性启动子构建了一个肝细胞特异性多功能表达载体，它可以同时过表达人IL-10和敲低CCL 5和FKN的表达。该载体可以通过减少肝脏NK细胞募集和血清IFN-γ和TNF-α来高效地减轻腺病毒诱导的急性肝炎。该多功能载体可通过非病毒（流体动力学注射）和病毒（腺病毒）途径递送，并保持长期功能（在小鼠中超过1个月）。我们的研究结果提示了一种可能的策略，通过调节多个免疫基因来改善腺病毒诱导的急性肝损伤。这种新型的多功能载体在多基因和复杂的肝脏疾病如恶性肿瘤和肝炎等与多基因疾病相关的疾病中具有广泛和实际的用途。免疫学杂志，2013，190：4821-4829。
Adenovirus or adenoviral vectors were reported to induce serious liver inflammation in an NK cell-dependent manner, which limits its clinical applicability for liver gene therapy. We tried to develop an efficient liver-directed therapeutic approach to control hepatic NK cell function via simultaneously manipulating multiple immune genes. Based on our previous study, we found that CCL5 knockdown synergistically enhanced the attenuating effect of silencing CX3CL1 (fractalkine [FKN]) in adenovirus-induced acute liver injury. In addition, the combined treatment of human IL-10 expression with FKN knockdown would further strengthen the protective effect of silencing FKN. We used a hepatocyte-specific promoter to construct a hepatocyte-specific multiple function vector, which could simultaneously overexpress human IL-10 and knock down CCL5 and FKN expression. This vector could attenuate adenovirus-induced acute hepatitis highly efficiently by reducing liver NK cell recruitment and serum IFN-gamma and TNF-alpha. The multiple function vectors could be delivered by nonviral (hydrodynamic injection) and viral (adenovirus) approaches, and maintained long-term function (more than 1 month in mice). Our results suggest a possible strategy to ameliorate the acute liver injury induced by adenovirus by modulating multiple immune genes. The novel multifunction vector has an extensive and practical use for polygenic and complex liver diseases such as malignancies and hepatitis, which correlate with multiple gene disorders. The Journal of Immunology, 2013, 190: 4821-4829.