The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors
The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors
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DOI：
10.1128/jvi.71.11.8798-8807.1997
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发表时间：
1997-11-01
影响因子：
5.4
通讯作者：
Kay, MA
中科院分区：
文献类型：
--
作者：
Lieber, A;He, CY;Kay, MA
全身应用第一代腺病毒可引起肝脏的致病效应。为了揭开腺病毒输注后早期肝脏毒性的机制，特别是巨噬细胞激活和病毒基因在转导的靶细胞中的表达的作用，将缺乏早期和晚期基因表达的第一代腺病毒或腺病毒载体注射到Kupffer细胞短暂耗竭后的C3H/HeJ小鼠。观察血清促炎症细胞因子肿瘤坏死因子(TNF)和白介素6(IL-6)水平与肝损伤、细胞凋亡和肝细胞DNA合成的关系。虽然库普弗细胞耗尽几乎消除了腺病毒诱导的肿瘤坏死因子的释放，但它导致了更强劲的IL-6释放，但在接受缺失的腺病毒的动物中，这些反应大大减少。尽管存在数量上的差异，但无论Kupffer细胞处于何种状态，第一代或被删除的腺病毒载体注射后几分钟内就观察到了NF-kappa B的激活，这表明这种诱导与病毒颗粒对肝细胞的直接作用有关。以血清谷丙转氨酶升高和炎性细胞浸润为指标的早期肝毒性依赖于腺病毒介导的早期基因表达和完整的Kupffer细胞功能，Kupffer细胞去除对腺病毒介导的肝细胞凋亡几乎没有影响，但确实增加了肝细胞DNA的合成。最后，Kupffer细胞耗尽降低了转基因(人α1-抗胰蛋白酶[HAAT])表达的持久性，这与更明显的针对HAAT的体液免疫反应有关。对静脉注射腺病毒后发生的这些事件的阐明将对开发新的载体和降低毒性的转移技术具有重要意义。
Systemic application of first-generation adenovirus induces pathogenic effects in the liver. To begin unraveling the mechanisms underlying early liver toxicity after adenovirus infusion, particularly the role of macrophage activation and expression of viral genes in transduced target cells, first-generation adenovirus or adenovirus vectors that lacked most early and late gene expression were administered to C3H/HeJ mice after transient depletion of Kupffer cells by gadolinium chloride treatment. Activation of NF-kappa B, and the serum levels of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) were studied in correlation with liver damage, apoptosis, and hepatocellular DNA synthesis. While Kupffer cell depletion nearly eliminated adenovirus-induced TNF release, it resulted in a more robust IL-6 release, These responses were greatly reduced in animals receiving the deleted adenovirus. Although there were quantitative differences, NF-kappa B activation was observed within minutes of first-generation or deleted adenovirus vector administration regardless of the status of the Kupffer cells, suggesting that the induction is related to a direct effect of the virus particle on the hepatocyte. Early liver toxicity as determined by serum glutamic-pyruvic transaminase elevation and inflammatory cell infiltrates appeared to be dependent on adenovirus-mediated early gene expression and intact Kupffer cell function, Kupffer cell depletion had little effect on adenovirus-mediated hepatocyte apoptosis but did increase hepatocellular DNA synthesis. Finally, Kupffer cell depletion decreased the persistence of transgene (human alpha 1-antitrypsin [hAAT]) expression that was associated with a more pronounced humoral immune response against hAAT. The elucidation of these events occurring after intravenous adenovirus injection will be important in developing new vectors and transfer techniques with reduced toxicity.