Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
J Surg Res. 2012 Dec;178(2):1003-14. doi: 10.1016/j.jss.2012.07.016. Epub 2012 Jul 26.
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.
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.
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.
Intragraft CXCL9 mRNA has a functionally important role in T-cell activation in liver allograft and serves as biomarker for ACR.
肝移植已成为治疗急性肝衰竭和各种终末期肝病的一种挽救生命且成熟的治疗方法。然而，急性细胞性排斥反应（ACR）是决定肝移植后长期移植物功能和存活率的关键因素之一，目前仍然没有可用的特定生物标志物来监测同种免疫反应。本研究旨在鉴定肝移植中 ACR 的分子生物标志物。
我们使用包含 44000 个人类探针的寡核苷酸微阵列分析了 35 个活体供肝移植后肝活检样本的基因表达谱，其中包括 13 个 ACR 样本（ACR 组；中度/轻度，6/7），13 个具有其他功能障碍的样本（非 ACR 组；丙型肝炎复发/缺血再灌注损伤（IRI）/非特异性炎症/小肝综合征，5/4/3/1），和 9 个无肝功能障碍的样本（方案组）。我们基于微阵列结果选择了 113 个有信息的基因，并采用网络分析可视化 ACR 中的关键调节剂。我们选择了 6 个调节剂（CXCL9、GZMB、CCL19、GBP2、LAIR1 和 CDC25A），并在 23 个独立的活检样本中验证了其可重复性，并在连续样本中研究了其对排斥反应治疗的反应。
网络分析显示了三个最重要的子网，其中 NF-κB、MAPK 和 IFNG 是中心枢纽。在选定的调节剂中，CXCL9 mRNA 的移植物内表达水平上调最明显，且对同种免疫状态敏感。
肝移植中 CXCL9 mRNA 的移植物内表达具有重要的 T 细胞激活功能，可作为 ACR 的生物标志物。
