Chen Qingfeng, Wei Haiming, Sun Rui, Zhang Jian, Tian Zhigang
Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
Hepatology. 2008 Feb;47(2):648-58. doi: 10.1002/hep.21993.
Gene therapy using adenovirus vectors may induce acute liver injury. Tissue injury induced by an adenovirus is likely associated with elevated expression of the Cys-X3-Cys chemokine ligand 1 (CX(3)CL1)/fractalkine (FKN) protein at the site of inflammation. However, the extent to which the actions of FKN contribute to liver injury remains unclear. We induced acute liver injury in mice by a hydrodynamics-based injection of adenovirus vector, which was confirmed to depend on the presence of natural killer (NK) cells and NK-dependent interferon-gamma (IFN-gamma). When the transferred adenovirus vector was inserted with the FKN gene, the severity of liver injury increased with much more Cys-X3-Cys chemokine receptor 1 (CX(3)CR1)-positive NK cell recruitment into the liver because of exogenous overproduction of FKN protein. Moreover, when production of endogenous FKN protein was silenced by inserting FKN-small interfering RNA into the adenovirus vector or was neutralized by an FKN-specific antibody, the adenovirus-induced acute severe liver injury was notably prevented with much lower hepatic NK cell infiltration and a significant reduction in the serum levels of IFN-gamma.
Our findings suggest a strategy to prevent or alleviate adenovirus vector-induced acute liver injury by blocking FKN-CX(3)CR1 interaction in adenovirus vector-based gene therapy.
使用腺病毒载体的基因治疗可能会诱发急性肝损伤。腺病毒诱导的组织损伤可能与炎症部位Cys-X3-Cys趋化因子配体1(CX(3)CL1)/fractalkine(FKN)蛋白表达升高有关。然而,FKN的作用在多大程度上导致肝损伤仍不清楚。我们通过基于流体动力学的腺病毒载体注射在小鼠中诱导急性肝损伤,证实这依赖于自然杀伤(NK)细胞和NK依赖的干扰素-γ(IFN-γ)的存在。当转移的腺病毒载体插入FKN基因时,由于FKN蛋白的外源性过量产生,更多Cys-X3-Cys趋化因子受体1(CX(3)CR1)阳性NK细胞募集到肝脏,肝损伤的严重程度增加。此外,当通过将FKN小干扰RNA插入腺病毒载体使内源性FKN蛋白的产生沉默或用FKN特异性抗体中和时,腺病毒诱导的急性严重肝损伤得到显著预防,肝NK细胞浸润明显减少,血清IFN-γ水平显著降低。
我们的研究结果提示了一种在基于腺病毒载体的基因治疗中通过阻断FKN-CX(3)CR1相互作用来预防或减轻腺病毒载体诱导的急性肝损伤的策略。