Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors
Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors
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DOI：
10.1002/hep.24625
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发表时间：
2012-01-01
期刊：
影响因子：
13.5
通讯作者：
Buening, Hildegard
中科院分区：
文献类型：
--
作者：
Hoesel, Marianna;Broxtermann, Mathias;Buening, Hildegard
腺相关病毒载体（rAAV）经常用于基因治疗试验。虽然rAAV载体具有低免疫原性，但可诱导体液以及T细胞应答。虽然前者限制了载体的再应用，但细胞毒性T细胞的扩增与肝脏炎症和转导肝细胞的损失相关。由于适应性免疫应答是先天免疫系统识别的结果，我们的目的是表征rAAV在原代人肝细胞和非实质肝细胞中引起的细胞自主免疫应答。令人惊讶的是，枯否细胞，而且肝窦内皮细胞，安装响应rAAV，而rAAV 2和rAAV 8都没有被肝细胞识别。病毒衣壳在细胞表面被Toll样受体2感知为病原体相关的分子模式。在浆细胞样树突状细胞中观察到的Toll样受体9介导的识别相反，rAAV在原代人肝细胞中的免疫识别没有诱导I型干扰素应答，但通过激活核因子？B。结论：使用原代人肝细胞，我们确定了一种新的机制rAAV识别在肝脏中，表明传感rAAV颗粒的替代手段已经发展。最大限度地减少这种识别将是改善rAAV介导的基因转移和减少临床试验中由于针对rAAV的免疫应答而引起的副作用的关键。（肝病学2012;55：287297）
Adeno-associated viral vectors (rAAV) are frequently used in gene therapy trials. Although rAAV vectors are of low immunogenicity, humoral as well as T cell responses may be induced. While the former limits vector reapplication, the expansion of cytotoxic T cells correlates with liver inflammation and loss of transduced hepatocytes. Because adaptive immune responses are a consequence of recognition by the innate immune system, we aimed to characterize cell autonomous immune responses elicited by rAAV in primary human hepatocytes and nonparenchymal liver cells. Surprisingly, Kupffer cells, but also liver sinusoidal endothelial cells, mounted responses to rAAV, whereas neither rAAV2 nor rAAV8 were recognized by hepatocytes. Viral capsids were sensed at the cell surface as pathogen-associated molecular patterns by Toll-like receptor 2. In contrast to the Toll-like receptor 9mediated recognition observed in plasmacytoid dendritic cells, immune recognition of rAAV in primary human liver cells did not induce a type I interferon response, but up-regulated inflammatory cytokines through activation of nuclear factor ?B. Conclusion: Using primary human liver cells, we identified a novel mechanism of rAAV recognition in the liver, demonstrating that alternative means of sensing rAAV particles have evolved. Minimizing this recognition will be key to improving rAAV-mediated gene transfer and reducing side effects in clinical trials due to immune responses against rAAV. (Hepatology 2012;55:287297)