Presenter: Marta, Lopez, Barceona, Spain
Authors: Marta Lopez, Carlos Benitez, Juan Jose Lozano, Marc Martinez-Llordella, Maria Londoño, Stefan Tomiuk, Uwe Janssen, Jacques Pirenne, Tommaso Manzia, Antonio Rimola, Giuseppe Tisone, Alberto Sanchez-Fueyo
Introduction: In contrast to other transplantation settings, the molecular characteristics of acute cellular rejection in human liver transplantation have not been adequately defined. In order to simultaneously assess the peripheral blood and liver tissue molecular profile of liver recipients undergoing acute rejection, we sequentially collected biological samples from recipients enrolled in a prospective multicenter European immunosuppression withdrawal clinical trial and conducted microarray gene expression profiling.
Methods: 96 liver recipients (>3 years after tx) were enrolled in the trial. Immunosuppression was gradually discontinued over a 6-9 month: the procedure was successful in 40 patients, while the remaining 56 recipients rejected during weaning. In rejecting patients RNA was extracted from liver biopsies obtained at baseline and at the time of rejection and processed on Illumina whole-genome expressionmicroarrays.In addition, RNAs obtained from sequential whole blood samples were hybridized onto the custom RISET 2.0 microarray (Agilent oligonucleotide microarray comprising 5,069 transplant-relevant probes).
Results: Rejection was associated with significant changes in the expression of 330 genes in liver tissue and 164 genes in blood (FDR<5%). Rejecting grafts exhibited an exuberant inflammatory response characterized by the upregulation of chemokines (CXCL10, CXCL9), cytokines (IL32, IL8), immune-activation markers (CD44, CD83, Stat1, CD69, CTLA4) and cytotoxicity-relates molecules (PRF1, GZMA, CD8A, CD3D). In contrast, blood expression changes were smaller in their magnitude and mainly characterized by up- and down-regulation of metabolism-related genes, with minor contribution from immunostimulatory genes. Some overlaps between blood and tissue were however noted, namely CXCL10, CD74, CDC20, CCNB2, HLA-DMB.
Conclusions: In liver transplantation acute rejection is associated with significant, but only minimally overlapping, gene expression changes in liver tissue and in blood. The specificity of liver allografts should be taken into account when employing transcriptional biomarkers developed in other transplantation settings.
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