Singh, HD; (2015) Immune cell interactions with stellate cells modulating HBV-related liver fibrosis (None,, Trans.). Doctoral thesis , UCL (University College London).

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Abstract

Chronic infection with hepatitis B virus is a global health issue, leading to liver cirrhosis and hepatocellular carcinoma that accounts for more than six hundred thousand deaths annually. Recent work has focused on the role of Natural killer (NK) cells in liver fibrosis in other contexts. In CHB, NK cells have been shown to play an anti-viral as well as an immunoregulatory role. Here we investigate the role of NK cells in the context of CHB-driven liver fibrosis, using primary hepatic stellate cells (HSC) isolated from healthy human liver margins. Our results demonstrate that NK cells from CHB patients have a highly variable and limited potential to kill hepatic stellate cells, which is increased in patients with progressive liver fibrosis, is further enhanced by interferon-alpha pre-activation in vitro and is abrogated by antiviral therapy with nucleos(t)ide inhibitors. We have explored the role of the death ligand TRAIL expressed on NK cells in inducing apoptosis of stellate cells that express high levels of the death-inducing receptor TRAIL-R2. We observed that blockade of TRAIL on the NK cells was only able to reduce killing of HSC in selected cases but not in the whole cohort, suggesting other levels of regulation. Moreover TRAIL ligand (SuperKillerTRAIL) treatment of primary HSC did not induce a degree of apoptosis commensurate with their high expression of the death-inducing receptor TRAIL-R2. We therefore probed the expression of the inhibitory receptors TRAIL-R3 and R4. We found expression of these receptors on primary human HSC both ex vivo and after in vitro culture. The level of expression of TRAIL-R4 showed a remarkably strong correlation with the susceptibility of primary HSC to undergo apoptosis. Furthermore, blockade of these inhibitory receptors rendered primary HSC more susceptible to apoptosis by SuperKillerTRAIL and by TRAIL-expressing NK cells. Our results are the first to demonstrate a functional role for TRAIL- R3 and -R4 in regulating susceptibility to apoptosis in primary cells. These novel findings will help us to define potential biomarkers and therapeutic targets for liver fibrosis.

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