Integrative omics and phase IIa clinical trial identify TNF as key node in autoimmune hepatitis

J o u r n a l P r e -p r o o f identifies IL-15 and TNF as central drivers of T cell-mediated cytotoxicity, offering new precision targets for intervention.The successful use of infliximab as a steroid-free therapy in a phase II trial marks a pivotal step toward safer, more specific treatment options for AIH patients.This research not only advances our understanding of AIH pathogenesis, but also sets the stage for broader application of immune-targeted therapies in autoimmune liver diseases. Highlights Type I cytokines, including TNF and the corresponding pro-inflammatory downstream signaling, are central to the hepatic immune response in AIH. AIH pathology can be sustained by a specific network of tissue-resident CD4 + and CD8 + memory T cells, myeloid cells, and hepatocytes, with TNF acting as one of the cytokines linking the cellular nodes of this network. IL15-induced cytotoxic auto-aggression by CD8 + T cells can kill hepatocytes, which is enhanced in the presence of CD4 + T cell-derived TNF. Anti-TNF treatment demonstrates efficacy as an alternative to steroid-based induction therapy