Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors
Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors
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DOI：
10.1038/sj.mt.6300031
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发表时间：
2007-02-01
影响因子：
12.4
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Cerullo, Vincenzo;Seiler, Michael P.;Lee, Brendan
全身性腺病毒基因替代疗法临床应用的主要障碍是宿主先天免疫反应。尽管最近的研究试图表征对系统施用的辅助依赖性腺病毒载体（HD-Ad）的这种反应的细胞基础，但识别病毒载体所需的先天免疫库的潜在分子成分尚未确定。在这里，我们证明初级巨噬细胞可以通过 Toll 样受体 9 (TLR9) 感知 HD-Ad 载体，并通过增加促炎细胞因子分泌来做出反应。此外，TLR9 传感参与体内对 HD-Ad 的快速先天免疫反应。 TLR9 缺陷会减弱对 HD-Ad 的先天免疫反应，而 TLR9 阻断则会减少静脉注射载体后的急性炎症反应。此外，HD-Ad 独立于 TLR9 功能上调 TLR9 基因表达，表明其他先天信号通路与 TLR9 协同工作。对腺病毒先天免疫反应成分的鉴定将有助于开发旨在增加全身递送的腺病毒载体的最大耐受剂量的组合疗法。
A major obstacle to the clinical application of systemic adenoviral gene replacement therapy is the host innate immune response. Although recent studies have attempted to characterize the cellular basis for this response to systemically administered helper-dependent adenoviral vector (HD-Ad), the underlying molecular components of the innate immune repertoire required to recognize the viral vector have yet to be identified. Here, we show that primary macrophages can sense HD-Ad vectors via the Toll-like Receptor 9 (TLR9) and respond by increasing pro-inflammatory cytokine secretion. Moreover, TLR9 sensing is involved in the rapid innate immune response to HD-Ad in vivo. TLR9 deficiency attenuates the innate immune response to HD-Ad, whereas TLR9 blockade reduces the acute inflammatory response after intravenous injection of the vector. Moreover, HD-Ad upregulates TLR9 gene expression independent of TLR9 function, suggesting that additional innate signaling pathways work cooperatively with TLR9. The identification of the components of the innate immune response to adenovirus will facilitate the development of combinatorial therapy directed at increasing the maximal tolerated dose of systemically delivered adenoviral vectors.