While liver transplantation is the treatment of choice for end-stage liver diseases, its success is compromised by the need to administer life-long immunosuppression, which negatively impacts on long-term outcomes. This emphasizes the need for the identification of biomarkers of successful immunosuppression (IS) withdrawal (operational tolerance). Our research group has pioneered the use of molecular profiling tools to characterize IS-free tolerant liver recipients. Thus, we recently completed a multi-centre IS withdrawal trial that included 102 liver recipients, 41 of whom achieved a successful drug discontinuation (TOL) and 57 rejected (Non-TOL). To understand the influence of miRNA regulation in the establishment of liver allograft tolerance, we collected liver biopsies before IS withdrawal was initiated and analyzed miRNA expression by small RNA sequencing. Employing a training set comprising liver biopsies from 12 TOL and 10 Non-TOL hepatitis C (HCV)-negative recipients, we identified 9 differential miRNAs out of 1,033 expressed human mature miRNAs (FC>1.5, p<0.05). The expression of these 9 miRNAs could discriminate TOL from Non-TOL recipients when employing principal component analysis. The differential expression of the most informative miRNA, miR-193a-3p, was confirmed by qPCR in an independent set of 14 TOL and 14 Non-TOL. miR-193a-3p was significantly over-expressed in TOL samples (p=0.011, fold change= 2.98) and exhibited a high predictive value with a ROC AUC of 0.79 (p=0.010). Thus, the use of a sole miRNA could be useful in the prediction of IS withdrawal outcome. Furthermore, we found miR-193a-3p is highly expressed in enriched hepatocytes compared to liver mononuclear cells or peripheral blood cells. Given a previously reported association between miR-193a-3p down-regulation and acetaminophen overdose-induced injury, we hypothesize that miR-193a-3p over-expression in tolerant patients protects hepatocytes from tissue damages elicited by IS withdrawal.

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