Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors
Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors
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DOI：
10.1128/jvi.76.9.4580-4590.2002
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发表时间：
2002-05-01
影响因子：
5.4
通讯作者：
Muruve, DA
中科院分区：
文献类型：
--
作者：
Zaiss, AK;Liu, Q;Muruve, DA
腺病毒载体由于先天免疫系统的激活和转导的靶细胞中多种趋化因子和细胞因子的表达而诱导感染组织的急性炎症。相比之下，腺相关病毒（AAV）载体在实验上或临床上与显著炎症无关。我们测试了AAV载体在体外诱导趋化因子表达和在体内激活先天免疫系统的能力。在人HeLa细胞和鼠肾上皮衍生细胞（REC细胞）中，腺病毒载体AdlacZ以剂量依赖性方式诱导多种炎性趋化因子的表达，包括RANTES、干扰素诱导蛋白10（IP-10）、白细胞介素-8（IL-8）、MIP-1 β和MIP-2。AAVlacZ的使用没有诱导这些趋化因子的表达高于基线水平，尽管根据Southern和狭缝印迹分析，其滴度比AdlacZ高40倍，并且细胞内AAVlacZ基因组的量更大。这一发现证实，趋化因子的AAVlacZ诱导的缺乏不是由于转导减少。在DBA/2小鼠中，静脉注射2.5 × 10（11）颗粒AAVlacZ导致肝脏肿瘤坏死因子α（TNF-α）、RANTES、IP-10、MIP-1 β、MCP-1和MIP-2 mRNA的快速诱导。然而，注射后6小时，趋化因子mRNA水平恢复到基线。正如预期的那样，给药10倍以下的AdlacZ导致诱导肝TNF-α和趋化因子mRNA，持续超过24小时后转导。静脉内给予2.5 × 10（11）粒AAVlacZ引发了中性粒细胞和CD 11b（+）细胞向肝脏的短暂浸润，这种反应与AdlacZ诱导的广泛炎症和毒性形成对比。Kupffer细胞耗竭消除了AAVlacZ，但没有AdlacZ诱导的趋化因子表达和中性粒细胞浸润。总之，这些结果表明，AAV载体激活先天性免疫系统的程度低于腺病毒载体，并为AAV与腺病毒载体相比炎症特性降低提供了可能的解释。
Adenovirus vectors induce acute inflammation of infected tissues due to activation of the innate immune system and expression of numerous chemokines and cytokines in transduced target cells. In contrast, adenoassociated virus (AAV) vectors are not associated with significant inflammation experimentally or clinically. We tested the ability of AAV vectors to induce the expression of chemokines in vitro and to activate the innate immune system in vivo. In human HeLa cells and murine renal epithelium-derived cells (REC cells) the adenovirus vector AdlacZ induced the expression of multiple inflammatory chemokines including RANTES, interferon-inducible protein 10 (IP-10), interleukin-8 (IL-8), MIP-1beta, and MIP-2 in a dose-dependent manner. The use of AAVlacZ did not induce the expression of these chemokines above baseline levels despite 40-fold-greater titers than AdlacZ and greater amounts of intracellular AAVlacZ genomes according to Southern and slot blot analysis. This finding confirmed that the lack of AAVlacZ induction of chemokine was not due to reduced transduction. In DBA/2 mice, the intravenous administration of 2.5 X 10(11) particles of AAVlacZ resulted in the rapid induction of liver tumor necrosis factor alpha (TNF-alpha), RANTES, IP-10, MIP-1beta, MCP-1, and MIP-2 mRNAs. However, 6 h following injection, chemokine mRNA levels returned to baseline. As expected, administration of 10-fold less AdlacZ caused an induction of liver TNF-alpha and chemokine mRNAs that persisted for more than 24 h posttransduction. Whereas intravenous administration of 2.5 X 10(11) particles of AAVlacZ triggered a transient infiltration of neutrophils and CD11b(+) cells into liver, this response stood in contrast to widespread inflammation and toxicity induced by AdlacZ. Kupffer cell depletion abolished AAVlacZ but not AdlacZ-induced chemokine expression and neutrophil infiltration. In summary, these results show that AAV vectors activate the innate immune system to a lesser extent than do adenovirus vectors and offer a possible explanation for the reduced inflammatory properties of AAV compared to adenovirus vectors.