IFNy-dependent immune responses are involved in the pathogenesis of PSC

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Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic interferon-γ (IFNγ)-producing lymphocytes have been documented in PSC patients, yet their functional role remains to be determined. The Mdr2-/- mouse is an established model to study mechanisms of chronic biliary inflammation and fibrosis during PSC. Using these animals as well as PSC patient samples, we asked whether IFNγ mediates the pathogenesis of PSC. Our previous studies showed that INFγ serum levels and NK cell numbers were increased in PSC patients. In Mdr2-/- mice, hepatic CD8+ T cells and NK cells were the main source of IFNγ and hepatic expression of IFNγ-inducible chemokines was enhanced. IFNγ changed the phenotype of hepatic CD8+ T cells and NK cells towards increased cytotoxicity and aggravated liver fibrosis.Therefore, we hypothesise that IFNγ is involved in hepatic effector cell migration and lymphocyte cytotoxicity during the pathogenesis of PSC.In our work programme, we will analyse phenotype and function of human and murine NK cells in more detail and perform depletion experiments in mice. As NK cells belong to the group of innate lymphoid cells (ILC) resembling ILC1 in phenotype and function, we will examine the role of ILC1 in PSC.To further determine the significance of lymphocyte cytotoxicity for PSC progression, we will generate Mdr2-/- x GzmB-/- and Mdr2-/- x Trail-/- mice and analyse disease pathology. To determine the contribution of CD8+ T cells to PSC pathogenesis, we will use an antigen-specific PSC model, where transfer of OVA-specific CD8+ T cells to Mdr2-/- x K14-OVAp mice was shown to aggravate liver damage. Whether this is mediated by IFNγ expression is not known. Therefore, we generated OT-I x Ifng-/- mice, in which OVA-specific CD8+ T cells do not express IFNγ. In collaborative studies, we will perform adoptive transfer experiments with Mdr2-/- x K14-OVAp mice to study the impact of antigen-specific, IFNγ-producing CD8+ T cells on liver damage and fibrosis. Moreover, CD8+ T cells from OT-1 x Gzmb-/- or OT-1 x Trail-/- mice will be used for adoptive transfer experiments to analyse the role of CD8+ T cell cytotoxicity. In a therapeutic approach, we will use an anti-p40 antibody to block IL-12 and IL-23 signalling in Mrd2-/- mice. An anti-p40 antibody (Ustekinumab) is licenced for treatment of inflammatory bowel diseases, which is frequently associated with PSC. In addition, we will generate Mdr2-/- x Cxcr3-/- mice, which lack a receptor for IFNγ-inducible chemokines, to evaluate the impact of IFNγ-mediated effector cell recruitment for PSC pathology. Moreover, we will study the therapeutic effect of CXCR3 antagonists in Mdr2-/- mice. Hence, we anticipate that investigation of IFNγ-dependent immune responses will provide novel options for treatment of PSC.