Molecular signatures discriminating different types of rejection in human liver transplants
Engel B, Alaswad A, Campos-Murguia A, Zoodsma M, Klingbeil A, Ruiz P, Crespo G, Chihab K, Bosselmann E, Heinrich S, Hartleben B, Jonigk D, Diaz A, Verboom M, Hallensleben M, Geffers R, Falk C, Ruff S, Lauber C, Skovgaard E, Karsdal M, Leeming D, Wedemeyer H, Xu C, Colmenero J, Jaeckel E, Li Y, Taubert R
Published in
Journal of Hepatology, Page S0168-8278(25)02338-4
Abstract
BACKGROUND&AIMS: The role of antibody-mediated rejection (AMR) after liver transplantation (LT) remains controversial. Chronic AMR (cAMR) is often subclinical and potentially missed without surveillance biopsies (svLbx). Transcriptome analysis previously characterized molecular changes in T cell-mediated rejection (TCMR) after solid organ transplantation. We aimed to identify molecular cAMR signatures after LT. METHODS: Indication and svLbx 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 (clinTCMR), and subclinical TCMR (subTCMR) compared to no histological rejection (NHR). RESULTS: Nineteen percent of LT recipients with donor-specific antibodies had cAMR in the training cohort. Fifty seven percent of cAMR patients had normal/near normal liver enzymes, recognized only by svLbx. CAMR was associated with subsequent cirrhosis development in 40-50% and displayed differentially expressed genes (DEGs) uniquely enriched in fibrogenesis-, complement activation- and TNFα-signaling-related pathways. ClinTCMR showed no such recurrent cirrhosis and DEGs uniquely enriched in antigen presentation-, interferon-signaling-, and T cell receptor-signaling-related pathways. SubTCMR was molecularly almost indistinguishable from NHR. There was a high degree of correlation in the DEGs between the training and two independent validation cohorts. CONCLUSIONS: We report transcriptome features of cAMR that is a unique molecular identity associated with inflammation and fibrogenesis as described in other solid organ transplantations and being linked to a high rate of liver graft failure.
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