Integrative omics and phase IIa clinical trial identify TNF as key node in autoimmune hepatitis.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Xu Yang, Weltzsch Jan Philipp, Kilian Christoph, Steglich Babett, Weiler-Normann Christina, Dudek Michael, Fackler Jonas, Wehmeyer Malte H, Tintelnot Joseph, Liebig Laura A, Steinmann Silja, Laschtowitz Alena, Horst Ludwig J, Schregel Ida, Sebode Marcial, Hartl Johannes, Casar Christian, Lu Jing, Schön Gerhard, Zapf Antonia, Bono Maria Rosa, Rosemblatt Mariana V, Nuñez Sarah, Castañeda Justine, Weidemann Sören Alexander, Kaiser Nico, Schwerk Maria, Kolster Manuela, Rattay Guido, Ulrich Hanna, Sivayoganathan Varshi, Song Ning, Krause Jenny, Böttcher Marius, Sagebiel Adrian, Wagner Jonas, Krebs Christian F, Puelles Victor G, Hübner Norbert, Tolosa Eva, Bonn Stefan, Huber Samuel, Knolle Percy A, Herkel Johannes, Adlung Lorenz, Schramm Christoph, Gagliani Nicola, Lohse Ansgar Wilhelm
Аннотация
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: Our studies revealed that myeloid cell and hepatocyte-derived IL-15 promotes cytotoxicity and proliferation of liver auto-aggressive CD8+ T cells. Full execution of their cytotoxic program is licensed by TNF derived from clonally expanded liver-resident CD4+ T cells. AIH hepatocytes respond to TNF by increasing expression of adhesion molecules, making them targets for both CD8+ and CD4+ 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.