Profiling of mouse and human liver diseases identifies targets for therapeutic treatment of autoimmune hepatitis

Abstract

Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and non-alcoholic steatohepatitis (NASH) are chronic liver diseases (CLDs) of distinct etiologies that represent a public health risk with limited therapeutic options. A common feature among CLDs is an aggressive T cell response resulting in destruction of liver tissue and fibrosis. Here, we assessed the presence and nature of T cell inflammation in late-stage human AIH, PSC and NASH and examined whether targeting the T cell response can improve disease pathology in a mouse model (Traf6ΔTEC) of spontaneous AIH. T cell infiltration and ensuing inflammatory pathways were present in human AIH and PSC and to a lesser extent in NASH. However, we observed qualitative differences in infiltrating T cell subsets and upregulation of inflammatory pathways among these diseases, while mouse and human AIH exhibited similar immunogenic signatures. While gene expression profiles differed among diseases, we identified 52 genes commonly upregulated across all diseases that included the JAK3 tyrosine kinase. Therapeutic targeting of chronic AIH with the JAK inhibitor tofacitinib reduced hepatic T cell infiltration, AIH histopathology and associated immune parameters in treated Traf6ΔTEC mice. Our results indicate that targeting T cell responses in established hepatic autoimmune inflammation is a feasible strategy for developing novel therapeutic approaches to treat AIH and possibly other CLDs irrespective of etiology.

Keywords: Autoimmune hepatitis; JAK3 kinase; Liver autoimmunity; PSC; T cells; Tofacitinib; mTECs.