Liver cirrhosis is the end-stage of a range of different chronic liver diseases including viral hepatitis, fatty liver disease, and alcoholic liver disease. The clinical management of patients with liver cirrhosis is limited by the lack of prognostic markers that predict disease progression and the lack of therapeutics that block the progression of liver cirrhosis. At present the only treatment option available for patients with cirrhosis is liver transplantation, however this procedure is limited by the availability of donor organs, the high cost (Euro140,000 per patient) and the requirement for life-long immune suppression. Definition of the biological mechanisms that contribute to the progression of liver cirrhosis will provide novel prognostic markers and therapeutic agents. The progression of liver cirrhosis is driven by dysfunctional immune responses, referred to as Cirrhosis-Associated Immune Dysfunction (CAID). CAID is characterised by systemic inflammation, which leads to reduced immune cell function, and is associated with liver failure requiring life-saving liver transplantation. While previous studies have described systemic inflammation in peripheral blood samples from cirrhotic patients, it is unclear how this inflammation affects tissue-resident immune cells present within the liver and how this results in deteriorating liver function. We and others have recently described an abundant population of liver-resident natural killer (NK) cells in humans which are functionally distinct from peripheral blood NK cells. Preliminary evidence suggests this population of liver-resident NK cells plays an important immune regulatory role. We hypothesise that the regulatory functions of liver-resident NK cells are lost in patients with liver cirrhosis. In this study, we aim to elucidate the effects of cirrhosis on liver-resident NK cell functions and define the immune interactions that influence the sensitivity of hepatocytes to apoptotic signals. These represent potential novel prognostic biomarkers and novel therapeutic targets for patients living with liver cirrhosis.
