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

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; John Bucuvalas; James Ferguson; Alberto Quaglia; Julia Sidorova; Maria Elstad; Abdel Douiri; Alberto Sánchez-Fueyo

doi:10.1016/j.jhep.2021.08.007

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

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 FengJohn Bucuvalas, James Ferguson, Alberto Quaglia, Julia Sidorova, Maria Elstad, Abdel Douiri, Alberto Sánchez-Fueyo

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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.

Original language	English
Pages (from-to)	1409-1419
Number of pages	11
Journal	Journal of Hepatology
Volume	75
Issue number	6
Early online date	23 Aug 2021
DOIs	https://doi.org/10.1016/j.jhep.2021.08.007
Publication status	Published - Dec 2021

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Vionnet, J., Miquel, R., Abraldes, J. G., Wall, J., Kodela, E., Lozano, J-J., Ruiz, P., Navasa, M., Marshall, A., Nevens, F., Gelson, W., Leithead, J., Masson, S., Jaeckel, E., Taubert, R., Tachtatzis, P., Eurich, D., Simpson, K. J., Bonaccorsi-Riani, E., ... Sánchez-Fueyo, A. (2021). Non-invasive alloimmune risk stratification of long-term liver transplant recipients. Journal of Hepatology, 75(6), 1409-1419. https://doi.org/10.1016/j.jhep.2021.08.007

@article{03271204443e49c48c0f3510b82ff970,

title = "Non-invasive alloimmune risk stratification of long-term liver transplant recipients",

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.",

author = "Julien Vionnet and Rosa Miquel and Abraldes, {Juan G} and Jurate Wall and Elisavet Kodela and Juan-Jose Lozano and Pablo Ruiz and Miguel Navasa and Aileen Marshall and Frederik Nevens and Will Gelson and Joanna Leithead and Steven Masson and Elmar Jaeckel and Richard Taubert and Phaedra Tachtatzis and Dennis Eurich and Simpson, {Kenneth J} and Eliano Bonaccorsi-Riani and Sandy Feng and John Bucuvalas and James Ferguson and Alberto Quaglia and Julia Sidorova and Maria Elstad and Abdel Douiri and Alberto S{\'a}nchez-Fueyo",

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{\textquoteright}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{\textquoteright}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{\textquoteright}s and St Thomas{\textquoteright} National Health Service (NHS) Foundation Trust and King{\textquoteright}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{\'e}t{\'e} Acad{\'e}mique Vaudoise and the Lausanne University Hospital . Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = dec,

doi = "10.1016/j.jhep.2021.08.007",

language = "English",

volume = "75",

pages = "1409--1419",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "6",

}

Vionnet, J, Miquel, R, Abraldes, JG, Wall, J, Kodela, E, Lozano, J-J, Ruiz, P, Navasa, M, Marshall, A, Nevens, F, Gelson, W, Leithead, J, Masson, S, Jaeckel, E, Taubert, R, Tachtatzis, P, Eurich, D, Simpson, KJ, Bonaccorsi-Riani, E, Feng, S, Bucuvalas, J, Ferguson, J, Quaglia, A, Sidorova, J, Elstad, M , Douiri, A & Sánchez-Fueyo, A 2021, 'Non-invasive alloimmune risk stratification of long-term liver transplant recipients', Journal of Hepatology, vol. 75, no. 6, pp. 1409-1419. https://doi.org/10.1016/j.jhep.2021.08.007

TY - JOUR

T1 - Non-invasive alloimmune risk stratification of long-term liver transplant recipients

AU - Vionnet, Julien

AU - Miquel, Rosa

AU - Abraldes, Juan G

AU - Wall, Jurate

AU - Kodela, Elisavet

AU - Lozano, Juan-Jose

AU - Ruiz, Pablo

AU - Navasa, Miguel

AU - Marshall, Aileen

AU - Nevens, Frederik

AU - Gelson, Will

AU - Leithead, Joanna

AU - Masson, Steven

AU - Jaeckel, Elmar

AU - Taubert, Richard

AU - Tachtatzis, Phaedra

AU - Eurich, Dennis

AU - Simpson, Kenneth J

AU - Bonaccorsi-Riani, Eliano

AU - Feng, Sandy

AU - Bucuvalas, John

AU - Ferguson, James

AU - Quaglia, Alberto

AU - Sidorova, Julia

AU - Elstad, Maria

AU - Douiri, Abdel

AU - Sánchez-Fueyo, Alberto

N1 - 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

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85116224955&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2021.08.007

DO - 10.1016/j.jhep.2021.08.007

M3 - Article

C2 - 34437910

SN - 0168-8278

VL - 75

SP - 1409

EP - 1419

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 6

ER -

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

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