Establishment of personalized immunosuppressive therapy based on molecular mechanisms of transplant immunological network

1.利用人体组织标本进行基因表达谱研究：检测192例自体小肠组织和208例移植肝组织中mdr1、CYP3A4、CYP3A5、CYP3A7和CYP3A43基因的表达水平和基因多态性。在活体供肝肝移植后，手术时天然小肠MDR1mRNA的表达水平可作为调整他克莫司初始剂量的重要生物标志物。移植肝细胞色素P3A5基因单核苷酸多态与术后他克莫司剂量递增显著相关。2.与免疫抑制药个体差异相关的药代动力学和药代动力学因素的阐明：手术时mdr1基因表达水平、细胞色素P3A5*3SNP和移植物与受者体重比以及经典的临床试验标记物被发现是人群…的统计学显著固定效应更多的运动分析。3.外周血白细胞基因表达信息的临床意义：针对活体供肝移植后急性细胞排斥反应的发生，以术后第3、7、14天外周血细胞总RNA片段为指标，检测其基因表达水平。血细胞中mdr1基因表达水平高于糖皮质激素受体(GR/NR3c1)的患者，他克莫司的靶向治疗水平更高。这些结果表明，组织中的各种蛋白质，如天然小肠和外周血白细胞的mdr1基因水平，以及移植物肝脏和天然肠道中的CYP3A5基因，是活体肝移植患者的药代动力学和药效学因素。通过整合这些分子因素，必须建立预防肝移植后急性细胞排斥反应的策略。然而，个体间对他克莫司反应差异的分子机制有待于进一步阐明。较少

1.Gene expression profile using human tissue specimens : The mRNA expression levels and genetic polymorphisms of MDR1,CYP3A4,CYP3A5,CYP3A7 and CYP3A43 were examined in the part of tissue specimens of native intestine (n=192) and graft liver (n=208). The mRNA expression level of MDR1 in the native small intestine at surgery was revealed to be a significant biomarker for adjustment of initial dosage of tacrolimus immediately after the living-donor liver transplantation. The data of single nucleotide polymorphism (SNP) of CYP3A5 in the graft liver was significantly associated with the dose escalation of tacrolimus by postoperative days.2.Clarification of the pharmacokinetic- and pharmacodymanic-factors to associate the individual variation of immunosuppressant : The mRNA expression level of MDR1 at surgery, CYP3A5*3 SNP and graft-vs-recipients body weight ratio as well as the classical clinical test markers were found to be the statistical significant fixed effects by the population pharm … More acokinetic analyses. In addition, we found that the frequency of posttransplant acute cellular rejection was successfully reduced to around 30% by the initial dosage regimen tacrolimus based on the evaluation of intestinal expression level of MDR1 at surgery.3.Clinical significance of gene expression information in the peripheral blood leukocyte : Focusing on the occurrence of acute cellular rejection after living-donor liver transplantation, the gene expression levels were examined with the total RNA fractions from the peripheral blood cells at postoperative days 3, 7 and 14. Using the pooled clinical samples over 500 points, the target therapeutic level of tacrolimus tended to be higher in the patients with high-expression level of MDR1 mRNA in blood cells rather than glucocorticoid receptor (GR/NR3C1).These results suggested that various proteins in the tissues such as the MDR1 mRNA level in the native small intestine and peripheral leukocytes and CYP3A5 genotype in the graft liver and native intestine were pharmacokinetic and pharmacodynamic factors in living-donor liver transplant patients. By integrating these molecular factors, the strategy to prevent acute cellular rejection after liver transplantation must be established. However, the molecular mechanisms of interindividual variation of the response against tacrolimus should be clarified in future. Less