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

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) experience increased mortality and severe side effects from non-specific immunosuppressive therapy, highlighting an urgent need for targeted treatment approaches. Here, we aimed to delineate the cellular and molecular network underlying AIH within its spatial context and to validate a key therapeutic target in a clinical trial. METHODS: We employed computational modelling, multi-omics analyses, and functional experiments to map the immune landscape of AIH. In addition, we conducted a steroid-free open-label phase IIa clinical trial using infliximab, a TNF-targeting antibody, in patients with AIH. RESULTS: T cells. In the clinical trial, targeting TNF with infliximab demonstrated efficacy as an entirely steroid-free AIH treatment. CONCLUSIONS: These findings elucidate the immune network in AIH and identify TNF as one of the central network nodes. Accordingly, our findings provide the basis for novel targeted, steroid-free immune therapies, including the use of infliximab. CLINICAL TRIAL NUMBER: European Union Clinical Trials Register (EudraCT No.: 2017-003311-19). IMPACT AND IMPLICATIONS: These findings have significant implications for the treatment of autoimmune hepatitis (AIH). By mapping the spatial and functional immune network within the AIH liver, this study 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 patients with AIH. 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.