Development of rational immunosuppressive therapy in organ transplantation based on pharmacogenomic and proteomic research

我们发现了预测大鼠心脏和肝脏移植急性排斥反应和免疫抑制剂治疗效果的基因标记。我们还发现了预测大鼠小肠移植急性排斥反应的蛋白标记物。大鼠心脏移植模型：DNA表达谱及实时荧光定量PCR分析显示，急性排斥反应显著诱导外周血6个候选基因（IRF1、PSMB9、TAP1、CTSS、NOS2、PIM1）的表达。环孢素可逆转诱导作用。环孢素谷浓度与基因表达的关系可以用s型Emax模型很好地描述。结果表明，这些候选基因的表达是预测排斥反应和免疫抑制剂治疗效果的良好指标。大鼠肝移植模型：我们在DNA芯片分析和定量PCR中发现急性排斥反应后外周血中四个基因的表达明显增加。免疫抑制剂降低了这些候选基因的表达。结果表明，这些基因在外周血中的表达可能是急性排斥反应和免疫抑制药物治疗效果的一个很好的预测指标。大鼠小肠移植模型：我们在外周血中发现了三种可能的生物标志物（10.1,13.0,14.8 kDa），反映了小肠移植后的急性排斥反应。其中，溶菌酶（14.8 kDa）可用于检测急性排斥反应和监测免疫抑制剂的药理作用，而迁移抑制因子相关蛋白(MRP)-8 （10.1 kDa）和MRP-14 （13.0 kDa）可用于检测早期同种异体移植排斥反应。

We found gene markers for predicting acute rejection and therapeutic effect of immunosuppressive agents in rat cardiac and liver transplantation. We also identified protein markers to predict acute rejection in rat small bowel transplantation.Rat cardiac transplantation model :Profiling of DNA expression followed by quantitative real-time PCR analysis revealed that the expression of six candidate genes (IRF1, PSMB9, TAP1, CTSS, NOS2, PIM1) in peripheral blood were significantly induced by acute rejection. The induction was reversed by cyclosporine administration. A relationship between the cyclosporine 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 were good predictors for rejection episode and therapeutic effect of immunosuppressive agents.Rat liver transplantation model :We found that the expression of four genes in peripheral blood were significantly increased by acute rejection in the DNA microarray analysis followed by quantitative PCR. Immunosuppressive agents reduced the expression of these candidate genes. The results suggested that the expression of these genes in peripheral blood would be a good predictor for acute rejection and therapeutic effect of immunosuppressive drugs.Rat small bowel transplantation model :We identified three possible biomarkers (10.1,13.0,14.8 kDa) in peripheral blood that reflected acute rejection after small bowel transplantation. Among them, lysozyme (14.8 kDa) may be useful for detecting acute rejection and for monitoring the pharmacological effects of immunosuppressants, whereas migration inhibitory factor-related protein (MRP)-8 (10.1 kDa) and MRP-14 (13.0 kDa) may be useful for detecting the early stage of allograft rejection.