Vα14iNKT Cells Promote Liver Pathology during Adenovirus Infection by Inducing CCL5 Production: Implications for Gene Therapy
Vα14iNKT Cells Promote Liver Pathology during Adenovirus Infection by Inducing CCL5 Production: Implications for Gene Therapy
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DOI：
10.1128/jvi.00605-10
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发表时间：
2010-09-01
影响因子：
5.4
通讯作者：
Aw, Tak Yee
中科院分区：
文献类型：
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作者：
Ajuebor, Maureen N.;Chen, Qingling;Aw, Tak Yee
复制缺陷型重组腺病毒是研究最广泛的复制缺陷型载体，可用于治疗人类遗传性疾病。然而，复制缺陷型腺病毒在基因治疗中的广泛临床应用正受到针对载体的强烈先天性和适应性免疫应答的诱导的阻碍，所述免疫应答在肝脏中引起有害作用。V α 14不变的自然杀伤T细胞（V α 14 iNKT细胞）是胸腺衍生的先天性T细胞，位于免疫应答的两个臂之间的界面处，并提供宿主防御的完全参与。肝内V α 14 iNKT细胞在复制缺陷型腺病毒感染过程中的病理生理作用尚不清楚，这是我们研究的主要焦点。我们的数据显示，肝内V α 14 iNKT细胞响应于腺病毒感染而被激活，以诱导显著水平的肝趋化因子（C-C基序）配体5（CCL 5）和随后的肝毒性。此外，肝内CCL 5的产生通过V α 14 iNKT细胞缺乏而选择性地减少。利用CCL 5缺陷型小鼠或V α 14 iNKT细胞缺陷型小鼠的体内研究表明，CCL 5缺陷型或V α 14 iNKT细胞缺陷型与肝脏病理学减轻相关。在阻断CCL 5受体的生物学效应后也观察到类似的结果。总之，我们已经确定了激活的肝内V α 14 iNKT细胞在积极影响肝脏CCL 5产生以促进急性肝脏炎症和损伤中的重要促炎作用。因此，我们的研究结果强调了阻断CCL 5与同源受体的相互作用是减轻与复制缺陷型腺病毒感染相关的肝脏病理学的重要潜在策略。
Replication-defective recombinant adenoviruses are the most widely studied replication-defective vectors for the potential treatment of inherited human diseases. However, broad clinical application of replication-defective adenoviruses in gene therapy is being hindered by the induction of vigorous innate and adaptive immune responses against the vector that cause deleterious effects in the liver. V alpha 14 invariant natural killer T cells (V alpha 14iNKT cells) are thymus-derived innate T cells at the interface between the two arms of the immune response and provide full engagement of host defense. The pathophysiological role of intrahepatic V alpha 14iNKT cells during replication-defective adenovirus infection is not known and is the main focus of our study. Our data showed that intrahepatic V alpha 14iNKT cells were activated in response to adenovirus infection to induce significant levels of hepatic chemokine (C-C motif) ligand 5 (CCL5) and subsequent liver toxicity. Moreover, intrahepatic CCL5 production was selectively reduced by V alpha 14iNKT cell deficiency. In vivo studies utilizing CCL5-deficient mice or V alpha 14iNKT cell-deficient mice demonstrated that CCL5 deficiency or V alpha 14iNKT cell deficiency was associated with reduced liver pathology. Similar results were seen after blocking the biological effects of the CCL5 receptors. In conclusion, we have identified an important proinflammatory role for activated intrahepatic V alpha 14iNKT cells in positively influencing hepatic CCL5 production to promote acute liver inflammation and injury. Therefore, our findings highlight the blockade of CCL5 interaction with a cognate receptor(s) as an important potential strategy to alleviate liver pathology associated with replication-defective adenovirus infection.