Indirect action of tumor necrosis factor-alpha in liver injury during the CD8+ T cell response to an adeno-associated virus vector in mice.
Indirect action of tumor necrosis factor-alpha in liver injury during the CD8+ T cell response to an adeno-associated virus vector in mice.
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DOI：
10.1002/hep.22869
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发表时间：
2009-06
期刊：
影响因子：
13.5
通讯作者：
Crispe, Ian Nicholas
中科院分区：
文献类型：
--
作者：
Giannandrea, Matthew;Pierce, Robert H.;Crispe, Ian Nicholas
CD 8 + T细胞可以通过两种不同的机制引起肝细胞损伤。除了它们的直接细胞毒性作用之外，还存在附带的肝损伤，其发生在细胞以抗原非依赖性方式被杀死时。虽然免疫效应细胞因子干扰素-γ（IFNγ）和肿瘤坏死因子-α（TNFα）都与各种形式的肝炎有关，但它们各自在直接和/或间接肝损伤中的作用仍不清楚。为了研究肝损伤的这些因素，我们开发了一种基于腺相关病毒基因治疗载体的CD 8 + T细胞介导的肝炎新实验模型。该载体用于将抗原递送至肝细胞，并过继转移对载体编码的转基因具有特异性的CD 8 + T细胞以产生肝脏免疫病理学。在该实验模型中，CD 8 + T细胞IFNγ作用于枯否细胞，诱导TNFα分泌和肝损伤。IFNγ和TNFα在这一损伤过程中都很重要，但TNFα是库普弗细胞功能的自分泌放大器，而不是肝细胞损伤的直接效应物。结论：TNFα间接促进肝损伤，而非直接肝毒性。IFNγ还通过枯否细胞活化间接导致肝损伤，同时通过诱导肝细胞MHC I类直接促进肝炎。原则上，可以通过开发靶向枯否细胞的疗法来改善这种免疫病理学间接机制，而不损害CD 8 + T细胞介导的抗病毒免疫。这将在慢性病毒性肝炎中具有巨大的治疗潜力。
CD8+ T-cells can cause hepatocellular injury by two distinct mechanisms. In addition to their direct cytotoxic effect, there is also collateral liver injury, which occurs when cells are killed in an antigen independent manner. While immune effector cytokines Interferon-gamma (IFNγ) and Tumor Necrosis Factor-alpha (TNFα) have both been implicated in various forms of hepatitis, their respective roles in direct and/or collateral liver damage remains unclear. In order to investigate these elements of liver injury, we have developed a new experimental model of CD8+ T-cell mediated hepatitis based on an Adeno-Associated Virus-based gene therapy vector. This vector is used to deliver antigen to hepatocytes, and CD8+ T-cells specific for the vector-encoded transgene are adoptively transferred to produce liver immunopathology. In this experimental model, CD8+ T-cell IFNγ acts on Kupffer cells, inducing TNFα secretion and liver injury. Both IFNγ and TNFα are important in this injury process, but TNFα acts as an autocrine amplifier of Kupffer cell function, rather than as a direct effector of hepatocellular damage. Conclusion: TNFα indirectly promotes liver damage, and is not a direct hepatotoxic agent. IFNγ also indirectly contributes to liver injury via Kupffer cell activation while, in parallel, directly promoting hepatitis via induction of hepatocyte MHC class I. In principle, it may be possible to ameliorate this immunopathologic indirect mechanism by developing therapies that target Kupffer cells, without impairing CD8+ T-cell mediated antiviral immunity. This would have great therapeutic potential in chronic viral hepatitis.
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影响因子：
6
作者：
Polakos, NK;Cornejo, JC;Pierce, RH
通讯作者：
Pierce, RH
影响因子：
13.5
作者：
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Sergent, O
影响因子：
15.3
作者：
LEHMANN, V;FREUDENBERG, MA;GALANOS, C
通讯作者：
GALANOS, C
DOI：
10.1084/jem.20061287
发表时间：
2007-03-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dunn C;Brunetto M;Reynolds G;Christophides T;Kennedy PT;Lampertico P;Das A;Lopes AR;Borrow P;Williams K;Humphreys E;Afford S;Adams DH;Bertoletti A;Maini MK
通讯作者：
Maini MK
DOI：
10.1152/ajpgi.00422.2005
发表时间：
2006-04-01
影响因子：
4.5
作者：
Schwabe, RF;Brenner, DA
通讯作者：
Brenner, DA