Intragraft transcriptome level of CXCL9 as biomarker of acute cellular rejection after liver transplantation.
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.


CONCLUSIONS
Intragraft CXCL9 mRNA has a functionally important role in T-cell activation in liver allograft and serves as biomarker for ACR.
Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. zm8t-asaoka@asahi-net.email.ne.jp
Tadafumi
T
Asaoka
Shigeru
S
Marubashi
Shogo
S
Kobayashi
Naoki
N
Hama
Hidetoshi
H
Eguchi
Yutaka
Y
Takeda
Masahiro
M
Tanemura
Hiroshi
H
Wada
Ichiro
I
Takemasa
Hidenori
H
Takahashi
Phillip
P
Ruiz
Yuichiro
Y
Doki
Masaki
M
Mori
Hiroaki
H
Nagano
D000208:Acute Disease; D000328:Adult; D000368:Aged; D015415:Biomarkers; D054370:Chemokine CXCL9 / Q000235:genetics* / Q000502:physiology; D005260:Female; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D016031:Liver Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D059467:Transcriptome
D015415:Biomarkers; C080810:CXCL9 protein, human; D054370:Chemokine CXCL9