Unconventional T-cells in bile duct inflammation

Inflammation in the bile ducts is an important clinical problem in patients with the chronic liver diseases primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Both of these conditions are important indications for liver transplantation. Previous studies have demonstrated a clear role for bacteria in the gut in PSC and PBC. In this project, we hypothesize that unconventional immune cells, that is immune cells that are not activated by proteins but rather by lipids and small molecular substances, can represent the link between the bacteria in the gut and the inflammation taking place in the bile ducts. We have now demonstrated presence of antigenes in bile that activate unconventional T-cells and published the results as a scientific article. We are also continuing the work to characterise the role of unconventional T-cells during cholestasis and the specific interactions on the interface in the bile ducts.

Unconventional T-lymphocytes are an abundant component of the immune system with an important function at mucosal surfaces of which natural killer T (NKT)-cells and mucosal associated invariant T (MAIT) cells are major subsets. The microbiome is important in defining the function of unconventional T-cells. The bile duct is ideally placed for studies of unconventional T-cells since the liver harbours the highest number of unconventional T-cells and the bile ducts represent the interface to the external milieu. The immunological process at this interface is relevant for the two diseases primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), both of which are important indications for liver transplantation. In the present project, it is hypothesised that unconventional T-cells play a major role in bile duct inflammation. This will be examined in four work-packages covering human studies and the use of advanced mouse models. In WP1 bile from patients will be examined for antigens potentially activating unconventional T-cells. In WP2 and WP3 we will use animal models of bile duct inflammation and test whether the inflammation is amenable to manipulation by altering the levels and activation of unconventional T-cells and by rendering the mice germ-free. In the final WP4 we will turn the attention back to the patients and examine unconventional T-cells at different stages of disease, perform in vitro experiments mimicking the disease process, and correlate these findings with the animal models. The work will be carried out by the applicant, one postdoc and one PhD student using locally established infrastructure and in collaboration with leading international experts in the field. PSC and PBC represent important health problem affecting young individuals. The present project aims to identify treatment targets that can potentially generate novel treatment with major implications for these patients.