Randomized trial investigating the utility of a liver tissue transcriptional biomarker in identifying adult liver transplant recipients not requiring maintenance immunosuppression
The maintenance of stable allograft status in the absence of immunosuppression (IS), known as operational tolerance, can be achieved in a small proportion of liver transplant recipients, but we lack reliable tools to predict its spontaneous development. We conducted a prospective, multicenter, biomarker-strategy design, IS withdrawal clinical trial to determine the utility of a predictive biomarker of operational tolerance. The biomarker test, originally identified in a patient cohort with high operational tolerance prevalence, consisted of a 5-gene transcriptional signature measured in liver tissue collected before initiating IS weaning. One hundred sixteen adult stable liver transplant recipients were randomized 1:1 to either arm A (IS withdrawal regardless of biomarker status) or arm B (IS withdrawal in biomarker-positive recipients). Immunosuppression withdrawal was initiated in 82 participants, rejection occurred in 54 (67.5%), and successful discontinuation of IS was achieved in 22 (27.5%), but only 13 (16.3%) met operational tolerance histologic criteria (10 in arm A; 3 in arm B). The biomarker test did not yield useful information in selecting patients able to successfully discontinue IS. Operational tolerance was associated with time posttransplant, recipient age, presence of circulating exhausted CD8<sup>+</sup> T cells, and a reduced number of immune synapses within the graft.
Authors
- James Ferguson (ORCID: https://orcid.org/0000-0002-2529-0409)
- Julien Vionnet (ORCID: https://orcid.org/0000-0002-1654-0488)
- Andrew Lesniak
- Eliano Bonaccorsi‐Riani (ORCID: https://orcid.org/0000-0002-5022-0234)
- Juan José Lozano (ORCID: https://orcid.org/0000-0001-7613-3908)
- Rosa Miquel (ORCID: https://orcid.org/0000-0001-7414-0186)
- Richard Taubert (ORCID: https://orcid.org/0000-0001-9270-2496)
- Elmar Jaeckel (ORCID: https://orcid.org/0000-0003-4108-7192)
- Anthony J. Demetris (ORCID: https://orcid.org/0000-0002-9582-3733)
- Elisavet Kodela (ORCID: https://orcid.org/0000-0002-4285-0842)
- Jurate Wall
- Marc Delord (ORCID: https://orcid.org/0000-0002-0455-6749)
- Steven Masson (ORCID: https://orcid.org/0000-0003-1041-9844)
- Pablo Ruíz (ORCID: https://orcid.org/0000-0002-5810-8802)
- Alberto Sánchez‐Fueyo (ORCID: https://orcid.org/0000-0002-8316-3504)
- Jorge P. Torres-Yaguana
- James F. Markmann (ORCID: https://orcid.org/0000-0002-2762-6535)
- Juliete A.F. Silva (ORCID: https://orcid.org/0000-0002-4543-5169)
- Dennis Eurich
- Joanna Leithead (ORCID: https://orcid.org/0000-0001-9443-4552)
- Marc Martínez‐Llordella (ORCID: https://orcid.org/0000-0003-1939-4102)
- Frederik Nevens (ORCID: https://orcid.org/0000-0003-2905-5112)
- Maria Elstad (ORCID: https://orcid.org/0000-0002-7882-7564)
- Abdel Douiri (ORCID: https://orcid.org/0000-0002-4354-4433)
- Juan G. Abraldeṣ (ORCID: https://orcid.org/0000-0003-3421-937X)
- Alberto Quaglia (ORCID: https://orcid.org/0000-0002-3333-3579)
- Miguel Navasa
- Will Gelson
- Aileen Marshall (ORCID: https://orcid.org/0000-0003-3283-6315)
- Phaedra Tachtatzis
- Kenneth J. Simpson
- Irene Rebollo‐Mesa
Institutions
- National Health Service (GB)
- Cliniques Universitaires Saint-Luc (BE)
- University of Alberta (CA)
- Royal Free London NHS Foundation Trust (GB)
- University of Pittsburgh (US)
- King's College London (GB)
- Queen Elizabeth Hospital Birmingham (GB)
- Leeds Teaching Hospitals NHS Trust (GB)
- The Royal Free Hospital (GB)
- Instituto de Salud Carlos III (ES)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Edinburgh Royal Infirmary (GB)
- Medizinische Hochschule Hannover (DE)
- Immune Tolerance Network (US)
- NIHR Birmingham Liver Biomedical Research Unit (GB)
- UPMC Health System (US)
- Hospital Clínic de Barcelona (ES)
- Royal Marsden Hospital (GB)
- Penn Center for AIDS Research (US)
- NIHR Newcastle Biomedical Research Centre (GB)
- University of Pittsburgh Medical Center (US)
- King's College Hospital (GB)
- Addenbrooke's Hospital (GB)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- NIHR Birmingham Biomedical Research Centre (GB)
- University College London (GB)
- Universitat de Barcelona (ES)
- Charité - Universitätsmedizin Berlin (DE)
- University of Pennsylvania (US)
- KU Leuven (BE)
Publication Details
- Journal
- American Journal of Transplantation
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1016/j.ajt.2024.12.002
- Citations
- 8
- Primary Topic
- Organ Transplantation Techniques and Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 4.58
Funders
- National Science Foundation
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research
- King's College London
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Centre Hospitalier Universitaire Vaudois
- National Institutes of Health
- Medical Research Council
- Efficacy and Mechanism Evaluation Programme
- NIHR Sheffield Biomedical Research Centre
- National Institute of Allergy and Infectious Diseases