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

Tadafumi Asaoka, Shigeru Marubashi, Shogo Kobayashi, Naoki Hama, Hidetoshi Eguchi, Yutaka Takeda, Masahiro Tanemura, Hiroshi Wada, Ichiro Takemasa, Hidenori Takahashi, Phillip Ruiz, Yuichiro Doki, Masaki Mori, Hiroaki Nagano

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Abstract

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.

Original languageEnglish
Pages (from-to)1003-1014
Number of pages12
JournalJournal of Surgical Research
Volume178
Issue number2
DOIs
Publication statusPublished - Dec 1 2012

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Liver Transplantation
Biomarkers
Liver
Allografts
Biopsy
Messenger RNA
End Stage Liver Disease
Acute Liver Failure
Living Donors
Graft Survival
Hepatitis C
Oligonucleotide Array Sequence Analysis
Reperfusion Injury
Liver Diseases
Inflammation
T-Lymphocytes
Transplants
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Asaoka, T., Marubashi, S., Kobayashi, S., Hama, N., Eguchi, H., Takeda, Y., ... Nagano, H. (2012). Intragraft transcriptome level of CXCL9 as biomarker of acute cellular rejection after liver transplantation. Journal of Surgical Research, 178(2), 1003-1014. https://doi.org/10.1016/j.jss.2012.07.016

Intragraft transcriptome level of CXCL9 as biomarker of acute cellular rejection after liver transplantation. / Asaoka, Tadafumi; Marubashi, Shigeru; Kobayashi, Shogo; Hama, Naoki; Eguchi, Hidetoshi; Takeda, Yutaka; Tanemura, Masahiro; Wada, Hiroshi; Takemasa, Ichiro; Takahashi, Hidenori; Ruiz, Phillip; Doki, Yuichiro; Mori, Masaki; Nagano, Hiroaki.

In: Journal of Surgical Research, Vol. 178, No. 2, 01.12.2012, p. 1003-1014.

Research output: Contribution to journalArticle

Asaoka, T, Marubashi, S, Kobayashi, S, Hama, N, Eguchi, H, Takeda, Y, Tanemura, M, Wada, H, Takemasa, I, Takahashi, H, Ruiz, P, Doki, Y, Mori, M & Nagano, H 2012, 'Intragraft transcriptome level of CXCL9 as biomarker of acute cellular rejection after liver transplantation', Journal of Surgical Research, vol. 178, no. 2, pp. 1003-1014. https://doi.org/10.1016/j.jss.2012.07.016
Asaoka, Tadafumi ; Marubashi, Shigeru ; Kobayashi, Shogo ; Hama, Naoki ; Eguchi, Hidetoshi ; Takeda, Yutaka ; Tanemura, Masahiro ; Wada, Hiroshi ; Takemasa, Ichiro ; Takahashi, Hidenori ; Ruiz, Phillip ; Doki, Yuichiro ; Mori, Masaki ; Nagano, Hiroaki. / Intragraft transcriptome level of CXCL9 as biomarker of acute cellular rejection after liver transplantation. In: Journal of Surgical Research. 2012 ; Vol. 178, No. 2. pp. 1003-1014.
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abstract = "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.",
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T1 - Intragraft transcriptome level of CXCL9 as biomarker of acute cellular rejection after liver transplantation

AU - Asaoka, Tadafumi

AU - Marubashi, Shigeru

AU - Kobayashi, Shogo

AU - Hama, Naoki

AU - Eguchi, Hidetoshi

AU - Takeda, Yutaka

AU - Tanemura, Masahiro

AU - Wada, Hiroshi

AU - Takemasa, Ichiro

AU - Takahashi, Hidenori

AU - Ruiz, Phillip

AU - Doki, Yuichiro

AU - Mori, Masaki

AU - Nagano, Hiroaki

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N2 - 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.

AB - 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.

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