Fiber-modified adenovirus vectors decrease liver toxicity through reduced IL-6 production
Fiber-modified adenovirus vectors decrease liver toxicity through reduced IL-6 production
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DOI：
10.4049/jimmunol.178.3.1767
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Mizuguchi, Hiroyuki
中科院分区：
文献类型：
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作者：
Koizumi, Naoya;Yamaguchi, Tomoko;Mizuguchi, Hiroyuki
腺病毒载体是基因治疗临床试验中最常用的病毒载体之一。然而，它们会引发强大的先天免疫反应和炎症反应。为了提高Ad载体基因治疗的疗效指数，需要阐明Ad载体诱导炎症和细胞因子/趋化因子产生的机制，以及开发更安全的载体。在本研究中，我们发现，纤维结节中含有多赖氨酸多肽的纤维修饰的Ad载体在静脉注射后，血清IL-6和天冬氨酸氨基转移酶(作为肝脏毒性的标志物)水平明显低于传统的Ad载体。虽然改良的Ad载体在肝脏中的转基因产量比传统的Ad载体高，但在给药后，转基因产量仍高于传统的Ad载体。RT-PCR分析表明，细胞因子、趋化因子和干扰素的主要表达部位是脾，而不是肝脏。脾CD11c(+)细胞分泌细胞因子。组织分布分析表明，修饰后的重组腺病毒载体的脾组织分布明显减少，反映了血清中IL-6水平的降低。抗IL-6R单抗可降低传统Ad载体的肝脏毒性，提示IL-6信号转导参与了肝脏毒性，而修饰的Ad载体降低肝脏毒性的部分原因是减少了IL-6的产生。本研究有助于了解系统给药的先天免疫宿主反应和肝脏毒性的生物学机制，并将有助于设计更安全的基因治疗方法，以降低强大的先天免疫和炎症反应。
Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c(+) cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.