Dual Roles of IFN-γ and IL-4 in the Natural History of Murine Autoimmune Cholangitis: IL-30 and Implications for Precision Medicine

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease with a long natural history. The pathogenesis of PBC is thought to be orchestrated by Th1 and/or Th17. In this study, we investigated the role of CD4(+) helper T subsets and their cytokines on PBC using our previous established murine model of 2-OA-OVA immunization. We prepared adeno-associated virus (AAV)-IFN-γ and AAV-IL-4 and studied their individual influences on the natural history of autoimmune cholangitis in this model. Administration of IFN-γ significantly promotes recruitment and lymphocyte activation in the earliest phases of autoimmune cholangitis but subsequently leads to downregulation of chronic inflammation through induction of the immunosuppressive molecule IL-30. In contrast, the administration of IL-4 does not alter the initiation of autoimmune cholangitis, but does contribute to the exacerbation of chronic liver inflammation and fibrosis. Thus Th1 cells and IFN-γ are the dominant contributors in the initiation phase of this model but clearly may have different effects as the disease progress. In conclusion, better understanding of the mechanisms by which helper T cells function in the natural history of cholangitis is essential and illustrates that precision medicine may be needed for patients with PBC at various stages of their disease process.