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New biomarkers for acute rejection and therapeutic effect of immunosuppressive drugs in organ transplantation

器官移植急性排斥反应的新生物标志物及免疫抑制药物的治疗效果

基本信息

批准号：
16590121
负责人：
MIHARA Kiyoshi
金额：
$ 2.37万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590121/
关键词：
organ transplantation immunosuppressive drugs biomarkers cDNA microarray rat rejection PK PD analysis

项目摘要

In organ transplantation, needle biopsy of allograft is a standard test for the diagnosis of acute rejection. However, sampling errors, biopsy-associated complications, and a time-consuming process are problem. The aim of this study is to search and identify new biomarkers for allograft rejection and therapeutic effect of immunosuppressive drugs by measuring gene expression profile in peripheral blood. We carried out the rat cardiac and liver transplantation to create three models, isograft, allograft, and allograft with cyclosporine (CsA). White blood cells in the peripheral bloods were collected to perform gene expression profiling using DNA microarray analysis. Ten candidate genes were selected in the DNA microarray analysis followed by quantitative PCR confirmation. The expression of all candidate genes in the peripheral blood were significantly elevated several days before graft loss due to acute rejection but showed no change in the isograft and CsA treated models. A relationship between the CsA trough concentration and the gene expression could be well described by a sigmoid Emax model. The results suggested that the expression of these candidate genes in peripheral blood were good predictors for rejection episode and therapeutic effect of CsA. Then, the gene expression in the peripheral blood was measured in pediatric patients with living-donor liver transplantation. The expression of five genes increased significantly two to six days before needle biopsy diagnosing acute rejection. A comprehensive analysis of the gene expression in peripheral blood of rat organ transplantation models results in the discovery of new biomarkers, which could be applied to the therapeutic use.

在器官移植中，同种异体移植物的穿刺活检是诊断急性排斥反应的标准试验。然而，取样误差、活检相关并发症和耗时的过程是问题。本研究的目的是通过检测外周血基因表达谱，寻找和鉴定新的生物标志物，用于同种异体移植排斥反应和免疫抑制剂的治疗效果。本实验采用大鼠心脏和肝脏移植，建立了同种、同种异体和环孢素A（CsA）联合移植模型。收集外周血中的白色血细胞，使用DNA微阵列分析进行基因表达谱分析。在DNA微阵列分析中选择10个候选基因，然后进行定量PCR确认。所有候选基因在外周血中的表达在移植物丢失前几天由于急性排斥反应而显著升高，但在同种移植物和CsA治疗的模型中没有显示出变化。CsA谷浓度与基因表达之间的关系可用S形Emax模型描述。结果提示，外周血中这些候选基因的表达可作为预测排斥反应发生和CsA疗效的良好指标。然后，在接受活体肝移植的儿科患者中测定外周血中的基因表达。在穿刺活检诊断急性排斥反应前2 ~ 6天，5个基因的表达显著增加。对大鼠器官移植模型外周血中基因表达的全面分析发现了新的生物标志物，可应用于治疗用途。