Trafficking of monocytes and their differentiation to dendritic cells and macrophages in the human liver

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Most liver diseases occur as a consequence of uncontrolled inflammation mediated by white blood cells recruited into the liver from the blood. White blood cells enter the liver via channels or sinusoids that are lined by specialised cells called endothelial cells which the white cells must bind to and migrate between before they can enter liver tissue. We propose that this process will a) determine the nature of the cells recruited and b) determine how those cells become activated and thereby the outcome of liver injury. We have developed complex test tube models in which combinations of human liver cells are grown under particular conditions that mimic the environment within the diseased liver sinusoids. We will use these models to investigate how white cells are recruited and how interactions with sinusoidal cells can define the activation status of the cells during their recruitment. Understanding this process will elucidate why in some circumstances white blood cells can promote the repair of the damaged liver whereas in other circumstances they amplify liver injury. We hope to use this information to develop new therapies to manipulate white blood cells in the liver in favour of repair rather than continuing liver damage and thereby to reverse inflammatory liver disease and prevent liver cirrhosis.