title: Molecular Characterization of Acute Cellular Rejection Occurring During Intentional Immunosuppression Withdrawal in Liver Transplantation.
abstract: Acute cellular rejection occurs frequently during the first few weeks following liver transplantation. During this period, its molecular phenotype is confounded by peri- and postoperative proinflammatory events. To unambiguously define the molecular profile associated with rejection, we collected sequential biological specimens from 55 patients at least 3 years after liver transplantation who developed rejection during trials of intentional immunosuppression withdrawal. We analyzed liver tissue and blood samples obtained before initiation of drug withdrawal and at rejection, alongside blood samples collected during the weaning process. Gene expression profiling was conducted using whole-genome microarrays and real-time polymerase chain reaction. Rejection resulted in distinct blood and liver tissue transcriptional changes in patients who were either positive or negative for hepatitis C virus (HCV). Gene expression changes were mostly independent from pharmacological immunosuppression, and their magnitude correlated with severity of histological damage. Differential expression of a subset of genes overlapped across all conditions. These were used to define a blood predictive model that accurately identified rejection in HCV-negative, but not HCV-positive, patients. Changes were detectable 1-2 mo before rejection was diagnosed. Our results provide insight into the molecular processes underlying acute cellular rejection in liver transplantation and help clarify the potential utility and limitations of transcriptional biomarkers in this setting.
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, Medical Research Council Centre for Transplantation, Faculty of Life Sciences and Medicine, King's College London University, King's College Hospital, Denmark Hill, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Bonaccorsi-Riani
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, Medical Research Council Centre for Transplantation, Faculty of Life Sciences and Medicine, King's College London University, King's College Hospital, Denmark Hill, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Pennycuick
authors.affiliation: Liver Unit, Hospital Clinic Barcelona, Institut d' Investigacions Biomedicas August Pi i Sunyer (IDIBAPS), Networked Biomedical Research Centre of Hepatic and Digestive Diseases (CIBERehd), University of Barcelona, Barcelona, Spain.
authors.forename: M-C
authors.initials: MC
authors.lastname: Londoño
authors.affiliation: Bioinformatics Platform, CIBEREHD, Barcelona, Spain.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: Liver Unit, Hospital Clinic Barcelona, Institut d' Investigacions Biomedicas August Pi i Sunyer (IDIBAPS), Networked Biomedical Research Centre of Hepatic and Digestive Diseases (CIBERehd), University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Benítez
authors.affiliation: AG Transplantationstoleranz, Charite Universitätsmedizin, Institut für Med. Immunologie, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: Liver Unit, Hospital Clinic Barcelona, Institut d' Investigacions Biomedicas August Pi i Sunyer (IDIBAPS), Networked Biomedical Research Centre of Hepatic and Digestive Diseases (CIBERehd), University of Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Picola
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bohne
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, Medical Research Council Centre for Transplantation, Faculty of Life Sciences and Medicine, King's College London University, King's College Hospital, Denmark Hill, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Llordella
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, Medical Research Council Centre for Transplantation, Faculty of Life Sciences and Medicine, King's College London University, King's College Hospital, Denmark Hill, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Miquel
authors.affiliation: Liver Unit, Hospital Clinic Barcelona, Institut d' Investigacions Biomedicas August Pi i Sunyer (IDIBAPS), Networked Biomedical Research Centre of Hepatic and Digestive Diseases (CIBERehd), University of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rimola
authors.affiliation: Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, Medical Research Council Centre for Transplantation, Faculty of Life Sciences and Medicine, King's College London University, King's College Hospital, Denmark Hill, London, UK.|Liver Unit, Hospital Clinic Barcelona, Institut d' Investigacions Biomedicas August Pi i Sunyer (IDIBAPS), Networked Biomedical Research Centre of Hepatic and Digestive Diseases (CIBERehd), University of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sánchez-Fueyo
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D006085:Graft Survival; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008107:Liver Diseases / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011446:Prospective Studies; D028761:Withholding Treatment
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents
keywords: basic (laboratory) research/science; clinical research/practice; genomics; liver allograft function/dysfunction; liver transplantation/hepatology; molecular biology; rejection: acute