BACKGROUND: Liver transplantation has been a life-saving and well-established treatment for acute liver failure and various end-stage liver diseases. However, acute cellular rejection (ACR) is one of the key factors that determine long-term graft function and survival after liver transplantation, and there are still no specific biomarkers available to monitor the alloimmune response. The aim of the present study was to identify molecular biomarkers for ACR in liver allograft. METHODS: We analyzed the gene expression profile using an oligonucleotide microarray covering 44,000 human probes in 35 liver biopsy samples after living donor liver transplant, which consisted of 13 samples with ACR (ACR group; moderate/mild, 6/7), 13 samples with other dysfunctions (non-ACR group; recurrent hepatitis C / ischemia/reperfusion injury (IRI)/ nonspecific inflammation / small-for-size syndrome, 5/4/3/1), and 9 samples without liver dysfunction (protocol group). We selected 113 informative genes based on microarray results and adopted the network analysis to visualize key modulators in ACR. We selected 6 modulators (CXCL9, GZMB, CCL19, GBP2, LAIR1, and CDC25A) and confirmed the reproducibility in 23 independent biopsy samples and investigated the response to the rejection treatment in sequential samples. RESULTS: Network analysis revealed the top three subnetworks, which had NF-κB, MAPK, and IFNG as central hubs. Among selected modulators, intragraft expression levels of CXCL9 mRNA was most upregulated and sensitive to alloimmune status. CONCLUSION: Intragraft CXCL9 mRNA has a functionally important role in T-cell activation in liver allograft and serves as biomarker for ACR.
BACKGROUND: Liver transplantation has been a life-saving and well-established treatment for acute liver failure and various end-stage liver diseases. However, acute cellular rejection (ACR) is one of the key factors that determine long-term graft function and survival after liver transplantation, and there are still no specific biomarkers available to monitor the alloimmune response. The aim of the present study was to identify molecular biomarkers for ACR in liver allograft. METHODS: We analyzed the gene expression profile using an oligonucleotide microarray covering 44,000 human probes in 35 liver biopsy samples after living donor liver transplant, which consisted of 13 samples with ACR (ACR group; moderate/mild, 6/7), 13 samples with other dysfunctions (non-ACR group; recurrent hepatitis C / ischemia/reperfusion injury (IRI)/ nonspecific inflammation / small-for-size syndrome, 5/4/3/1), and 9 samples without liver dysfunction (protocol group). We selected 113 informative genes based on microarray results and adopted the network analysis to visualize key modulators in ACR. We selected 6 modulators (CXCL9, GZMB, CCL19, GBP2, LAIR1, and CDC25A) and confirmed the reproducibility in 23 independent biopsy samples and investigated the response to the rejection treatment in sequential samples. RESULTS: Network analysis revealed the top three subnetworks, which had NF-κB, MAPK, and IFNG as central hubs. Among selected modulators, intragraft expression levels of CXCL9 mRNA was most upregulated and sensitive to alloimmune status. CONCLUSION: Intragraft CXCL9 mRNA has a functionally important role in T-cell activation in liver allograft and serves as biomarker for ACR.