Molecular signatures discriminating different types of rejection in human liver transplants

作者：Bastian Engel, Ahmed Alaswad, Alejandro Campos-Murguía, Martijn Zoodsma, Anne Klingbeil, Pablo Ruíz, Gonzalo Crespo, Kinan Chihab, Emily Bosselmann, Sophia Heinrich, Björn Hartleben, Danny Jonigk, Alba Díaz, Murielle Verboom, Michael Hallensleben, Robert Geffers, Christine S. Falk, Sergej Ruff, Chris Lauber, Emilie Skovgaard, M.A. Karsdal, Diana Julie Leeming, Heiner Wedemeyer, Cheng‐Jian Xu, Jordi Colmenero, Elmar Jaeckel, Yang Li, Richard Taubert · 发表于：Journal of Hepatology · 年份：2025 · DOI：10.1016/j.jhep.2025.06.036 · 被引用次数：6 · 研究领域：Organ Transplantation Techniques and Outcomes、Renal Transplantation Outcomes and Treatments、Liver Disease and Transplantation

BACKGROUND & AIMS: The role of antibody-mediated rejection (AMR) after liver transplantation (LT) remains controversial. Chronic AMR (cAMR) is often subclinical and may be missed without surveillance biopsies (svLbx). Transcriptome analyses have previously characterized molecular changes in T cell-mediated rejection (TCMR) after solid organ transplantation. We aimed to identify molecular signatures of cAMR after LT. METHODS: Indication and surveillance biopsies from two prospective institutional biorepositories were screened. We performed bulk RNA sequencing on liver biopsies (discovery cohort: n = 71; Hannover validation cohort: n = 58; Barcelona validation cohort: n = 29). Downstream analyses explored the molecular features of cAMR, clinical TCMR, and subclinical TCMR, compared to no histological rejection. RESULTS: Nineteen percent of LT recipients with donor-specific antibodies had cAMR in the training cohort. Of these patients, 57% had normal/near normal liver enzymes, with cAMR detected only by svLbx. cAMR was associated with subsequent cirrhosis in 40-50% of cases and exhibited differentially expressed genes (DEGs) uniquely enriched in pathways related to fibrogenesis, complement activation, and TNFα signaling. In contrast, clinical TCMR was not associated with recurrent cirrhosis and showed DEGs enriched in antigen presentation, interferon signaling, and T cell receptor signaling. Subclinical TCMR was molecularly almost indistinguishable from no histological rejection...