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Am J Transplant. 2016 Feb;16(2):484-96. doi: 10.1111/ajt.13488. Epub 2015 Oct 30.

Molecular Characterization of Acute Cellular Rejection Occurring During Intentional Immunosuppression Withdrawal in Liver Transplantation.

Author information

1
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.
2
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.
3
Bioinformatics Platform, CIBEREHD, Barcelona, Spain.
4
AG Transplantationstoleranz, Charite Universitätsmedizin, Institut für Med. Immunologie, Berlin, Germany.
5
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.

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.

KEYWORDS:

basic (laboratory) research/science; clinical research/practice; genomics; liver allograft function/dysfunction; liver transplantation/hepatology; molecular biology; rejection: acute

PMID:
26517400
DOI:
10.1111/ajt.13488
[Indexed for MEDLINE]
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