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

基于移植免疫网络分子机制建立个体化免疫抑制治疗

• 批准号: 16209005
• 负责人: INUI Ken-ichi
• 金额: $ 30.53万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209005/
• 关键词: immunosuppressant; absorptive barrier; drug metabolizing enzyme; transporter; liver transplantation; calcineurin; tacrolimus; cyclosoorine; 肝臓移植治療; immunosuppressant; absorptive barrier; drug metabolizing enzyme; transporter; liver transplantation; calcineurin; tacrolimus; cyclosoorine; 肝臓移植治療

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

1。使用人体组织样品的基因表达谱：在天然肠（n = 192）和移植叶（n = 208）的一部分中，在研究了MDR1，CYP3A4，CYP3A5，CYP3A7和CYP3A43的mRNA表达水平和遗传多态性水平和遗传多态性。手术中天然小肠中MDR1的mRNA表达水平揭示是在活肝移植后立即调节他克莫司的初始剂量的重要生物标志物。草肝中CYP3A5的单个核苷酸多态性（SNP）的数据与克莫司的剂量升级显着相关。发现移植-VS的体重比以及经典的临床测试标记是人群具有统计学上显着的固定作用……更多的动员分析。此外，我们发现，基于手术中MDR1的肠道表达水平的评估，初始剂量剂量型克罗莫司成功地将移植后急性细胞排斥的频率成功降低至30％。3。基因表达在外周血白细胞中的基因表达信息的核心表达意义：集中在急性细胞中的疾病，是在急性细胞的重点介绍了急性的疾病。在术后第3、7和14天，检查外周血细胞的总RNA级分。使用汇总的临床样品超过500点，他克莫司的目标治疗水平往往更高，而在血细胞中，MDR1 mRNA的高表达水平的患者往往更高。这些结果表明，组织中的各种蛋白质（例如本地小肠和周围白细胞中的MDR1 mRNA水平）以及移植肝脏和天然肠中的CYP3A5基因型是药物动力学和药物动力学因子的生物动力学因子。通过整合这些分子因子，必须确定肝移植后预防急性细胞排斥的策略。然而，将来应阐明反应对克莫司反应的个体差异的分子机制。较少的