New treatment targets in autoimmune hepatitis: detection using integrative omics and target validation in a proof of concept phase II clinical trial

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Standard immunosuppression for autoimmune hepatitis (AIH) is non-specific with corticosteroids as drug of choice for remission induction. An improved understanding of the underlying pathophysiology is needed and could enable a tailored therapeutic approach and avoid side effects associated with standard therapy. We combined systems and experimental immunology to map the cellular and molecular network involved in AIH and substantiated these findings by targeting tumor necrosis factor alpha (TNF), a key component of this network, in a clinical trial. Our computational models and functional experiments indicate that IL-15, produced by dendritic cells and macrophages, primes the cytotoxic activity of liver-resident CD8 T cells. The full activation of this cytotoxic pathway is driven by TNF released from clonally expanded, tissue-resident CD4 T cells. In response to TNF, hepatocytes from patients with AIH upregulate adhesion molecules for CD8 T cells and MHC class II molecules, making them susceptible to damage caused by both CD8 and CD4 T cells, perpetuating the inflammatory cycle. As a validation, we performed an open-label, proof-of-concept phase II trial using infliximab, a monoclonal antibody against TNF, as induction therapy of newly diagnosed, untreated AIH. We observed a rapid treatment response with 90% ALT reduction within 24 weeks from baseline with this entirely steroid-free treatment. These findings provide a detailed and unified view of the cellular and molecular mechanisms underlying AIH, and identify TNF as a treatable target. Publication History Article published online: 20 January 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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