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Non-invasive alloimmune risk stratification of long-term liver transplant recipients

Research output: Contribution to journalArticlepeer-review

Julien Vionnet, Rosa Miquel, Juan G Abraldes, Jurate Wall, Elisavet Kodela, Juan-Jose Lozano, Pablo Ruiz, Miguel Navasa, Aileen Marshall, Frederik Nevens, Will Gelson, Joanna Leithead, Steven Masson, Elmar Jaeckel, Richard Taubert, Phaedra Tachtatzis, Dennis Eurich, Kenneth J Simpson, Eliano Bonaccorsi-Riani, Sandy Feng & 7 more John Bucuvalas, James Ferguson, Alberto Quaglia, Julia Sidorova, Maria Elstad, Abdel Douiri, Alberto Sánchez-Fueyo

Original languageEnglish
JournalJournal of Hepatology
Early online date23 Aug 2021
DOIs
Accepted/In press3 Aug 2021
E-pub ahead of print23 Aug 2021

Bibliographical note

Funding Information: We are grateful to all the patients who participated in the study. We thank Dr Maria Meneghini and Dr Oriol Bestard (Hospital Bellvitge, Barcelona, Spain) for guidance regarding HLA molecular mismatch analyses, Dr Olivia Shaw (Clinical Transplantation Laboratory, Guy’s Hospital, London, United Kingdom) for her help in the interpretation of HLA typing and anti-HLA antibody data, and Matthias Niemann (PIRCHE) and Cynthia Kramer (HLA-EMMA) for helpful discussions. AD acknowledges funding support from the NIHR Applied Research Collaboration (ARC) South London at King’s College Hospital NHS Foundation Trust and the Royal College of Physicians. Funding Information: The work was supported by an award from the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) Programme (reference 13/94/55; to ASF), the Medical Research Council Centre for Transplantation, and the NIHR Biomedical Research Centre at Guy's and St Thomas? National Health Service (NHS) Foundation Trust and King's College London. JV was supported by the Swiss National Science Foundation (Early Postdoc.Mobility P2LAP3_181318 and Postdoc.Mobility P400PM_194501 grants), by the Fondation genevoise de bienfaisance Valeria Rossi di Montelera (Eugenio Litta grant), by the Soci?t? Acad?mique Vaudoise and the Lausanne University Hospital. Funding Information: The work was supported by an award from the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) Programme (reference 13/94/55; to ASF), the Medical Research Council Centre for Transplantation , and the NIHR Biomedical Research Centre at Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust and King’s College London. JV was supported by the Swiss National Science Foundation (Early Postdoc.Mobility P2LAP3_181318 and Postdoc.Mobility P400PM_194501 grants), by the Fondation genevoise de bienfaisance Valeria Rossi di Montelera (Eugenio Litta grant), by the Société Académique Vaudoise and the Lausanne University Hospital . Publisher Copyright: © 2021

King's Authors

Abstract

Background & Aims: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. Methods: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). Results: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. Conclusion: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. Lay summary: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.

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