Indirect Action of Tumor Necrosis Factor-Alpha in Liver Injury During the CD8+T Cell Response to an Adeno-Associated Virus Vector in Mice

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. Whereas immune effector cytokines interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) 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 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 IFN gamma acts on Kupffer cells, inducing TNF alpha secretion and liver injury. Both IFN gamma and TNF alpha are important in this injury process, but TNF alpha acts as an autocrine amplifier of Kupffer cell function, rather than as a direct effector of hepatocellular damage. Conclusions. TNF alpha indirectly promotes liver damage and is not a direct hepatotoxic agent. IFN gamma also indirectly contributes to liver injury through Kupffer cell activation while, in parallel, directly promoting hepatitis through induction of hepatocyte major histocompatability complex 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. (HEPATOLOGY 2009;49:2010-2020.)