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

JOURNAL OF HEPATOLOGY

卷:75

Article

Vionnet, Julien^1,2,3,4  Miquel, Rosa^1,2,5  Abraldes, Juan G.⁶  Wall, Jurate^1,2  Kodela, Elisavet^1,2  Lozano, Juan-Jose⁷  Ruiz, Pablo⁸  Navasa, Miguel⁸  Marshall, Aileen⁹  Nevens, Frederik¹⁰  Gelson, Will¹¹  Leithead, Joanna¹¹  Masson, Steven¹²  Jaeckel, Elmar¹³  Taubert, Richard¹³  Tachtatzis, Phaedra¹⁴  Eurich, Dennis¹⁵  Simpson, Kenneth J.¹⁶  Bonaccorsi-Riani, Eliano¹⁷  Feng, Sandy¹⁸  Bucuvalas, John^19,20  Ferguson, James²¹  Quaglia, Alberto⁹  Sidorova, Julia²²  Elstad, Maria²³  Douiri, Abdel²³  Sanchez-Fueyo, Alberto^1,2 

[1] Kings Coll London Univ, Inst Liver Studies, London, England

[2] Kings Coll Hosp London, London, England

[3] Univ Hosp Lausanne, Transplantat Ctr, Lausanne, Switzerland

[4] Univ Hosp Lausanne, Serv Gastroenterol & Hepatol, Lausanne, Switzerland

[5] Kings Coll Hosp London, Liver Histopathol Lab, London, England

[6] Univ Alberta, Ctr Excellence Gastrointestinal Inflammat & Immun, Div Gastroenterol, Liver Unit, Edmonton, AB, Canada

[7] Inst Salud Carlos III, Biomed Res Ctr Hepat & Digest Dis CIBEREHD, Bioinformat Platform, Madrid, Spain

[8] Hosp Clin Barcelona, Barcelona, Spain

[9] Royal Free Hosp, London, England

[10] Univ Hosp KU Leuven, Leuven, Belgium

[11] Addenbrookes Hosp, Cambridge, England

[12] Newcastle Upon Tyne Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England

[13] Hannover Med Sch, Hannover, Germany

[14] Leeds Teaching Hosp NHS Trust, Leeds, W Yorkshire, England

[15] Charite, Berlin, Germany

[16] Edinburgh Royal Infirm, Edinburgh, Midlothian, Scotland

[17] Clin Univ St Luc, Liver Transplant Unit, Brussels, Belgium

[18] Univ Calif San Francisco, Dept Surg, Div Transplantat, San Francisco, CA USA

[19] Mt Sinai Kravis Childrens Hosp, New York, NY USA

[20] Mt Sinai Hlth Syst, Recanati Miller Transplantat Inst, New York, NY USA

[21] Queen Elizabeth Hosp, Birmingham, W Midlands, England

[22] Univ Complutense, Inst Tecnol Conocimiento ITC, Campus Somosaguas, Madrid, Spain

[23] Kings Coll London, Sch Populat Hlth & Environm Sci, London, England

关键词: LT;    biomarkers;    non-invasive;    T cell-mediated rejection;    fibrosis;    geneexpression profiling;    tolerance;    FibroScan;    immunosuppression minimisation;    HLA epitope mismatch;    PIRCHE-II score;    DSA;   

DOI  :  10.1016/j.jhep.2021.08.007

来源: Elsevier

【 摘 要 】

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. (C) 2021 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

【 授权许可】

Free