Respective roles of TNF-α and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice
Respective roles of TNF-α and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice
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DOI：
10.1038/sj.gt.3302885
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发表时间：
2007-03-01
期刊：
影响因子：
5.1
通讯作者：
Perricaudet, M.
中科院分区：
文献类型：
--
作者：
Benihoud, K.;Esselin, S.;Perricaudet, M.
重组腺病毒(Ad)的免疫原性是其在基因治疗中应用的主要问题。腺病毒载体引发的抗体和细胞免疫反应阻碍了转基因的长期表达和有效的病毒管理。我们先前报道，白介素6和肿瘤坏死因子α分别在Ad的急性期和抗体反应中起重要作用。由于肿瘤坏死因子-α控制免疫反应和免疫系统的发育，我们在这里研究了通过Ad介导的二聚体小鼠TNFR1-Ig G融合蛋白对来自第二个Ad的转基因表达的阻断肿瘤坏死因子-α活性的后果。在野生型(IL-6(+/+))和IL-6缺陷型(IL-6‘)小鼠(IL-6’)静脉注射编码TNFR1-Ig的AdTNFR1-Ig和编码β-半乳糖苷酶或α1-抗胰蛋白酶的Ad，以分析肿瘤坏死因子-α和IL-6对肝脏基因转移效率的影响。阻断肿瘤坏死因子-α导致野生型和IL-6(/)小鼠的转基因表达增加，原因是炎症反应减少，巨噬细胞和NK细胞向肝脏募集减少。AdTNFR1-Ig处理的野生型小鼠对腺病毒颗粒和表达的转基因的抗体反应仅延迟，而AdTNFR1-Ig处理的IL-6(/)小鼠的抗体反应显著降低。最后，用临床批准的抗肿瘤坏死因子-α药物依那西普治疗小鼠，证实了在腺病毒载体的基因治疗过程中控制促炎细胞因子的重要性。
The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-alpha controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-alpha activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding beta-galactosidase or alpha 1-antitrypsin transgene in wild-type (IL-6(+/+)) but also in IL-6-deficient mice (IL-6') to analyze how TNF-alpha and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-alpha leads to increased transgene expression in both wild-type and IL-6(/) mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1-Ig- treated wild- type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6(/) mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-alpha drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.