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

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.人体组织标本基因表达谱：检测192例自体小肠和208例移植肝组织标本中MDR 1、CYP 3A 4、CYP 3A 5、CYP 3A 7和CYP 3A 43的mRNA表达水平和基因多态性。研究表明，手术时自体小肠中MDR 1的mRNA表达水平是活体肝移植后立即调整他克莫司初始剂量的重要生物标志物。移植肝中CYP 3A 5单核苷酸多态性（SNP）数据与术后他克莫司剂量递增显著相关。2.阐明与免疫抑制剂个体差异相关的药代动力学和药效学因素：手术时MDR 1 mRNA表达水平，CYP 3A 5 *3 SNP和移植物与受体的体重比以及经典的临床试验标记物被发现是群体药物统计学上显著的固定效应 ...更多信息 无动力学分析此外，我们发现，基于手术时肠道MDR 1表达水平的评估，他克莫司的初始剂量方案成功地将移植后急性细胞排斥反应的频率降低到30%左右。3.外周血白细胞基因表达信息的临床意义：针对活体肝移植术后急性细胞排斥反应的发生，在术后第3、7和14天用来自外周血细胞的总RNA级分检测基因表达水平。使用超过500个点的合并临床样本，血细胞中MDR 1 mRNA表达水平高的患者，他克莫司的靶向治疗水平往往较高，而糖皮质激素受体表达水平低的患者，他克莫司的靶向治疗水平较高（GR/NR3C1）这些结果表明，在移植肝和移植肝中的各种蛋白质，如天然小肠和外周血白细胞中的MDR 1 mRNA水平以及移植肝和天然小肠中的CYP 3A 5基因型，肠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子，必须建立预防肝移植术后急性细胞排斥反应的策略。然而，对他克莫司反应的个体间差异的分子机制应在未来澄清。少

项目成果

Tacrolimus therapy according to mucosal MDR1 levels in recipients of small bowel transplantation.

根据小肠移植受者粘膜 MDR1 水平的他克莫司治疗。

• 发表时间: 2004
• 期刊: Cli. Pharmacol Ther 75・4
• 作者: Masuda;S
• 通讯作者: S

Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract.

• DOI: 10.1016/j.bcp.2005.09.027
• 发表时间: 2005-12
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: T. Terada;Y. Shimada;Xiaoyue Pan;K. Kishimoto;T. Sakurai;R. Doi;H. Onodera;T. Katsura;M. Imamura;K. Inui

Surgical resection deteriorates gemcitabine-induced leucopenia in pancreatic cancer

手术切除会恶化吉西他滨引起的胰腺癌白细胞减少症

• 发表时间: 2004
• 期刊: Int J Clin Oncol 9・3
• 作者: Onoue;M
• 通讯作者: M

Pharmacodynamic analysis of tacrolimus and cyclosporine in patients of living-donor liver transplantation

他克莫司与环孢素在活体肝移植患者中的药效学分析

• 发表时间: 2005
• 期刊: Clin. Pharmacol. Ther 78・2
• 作者: Fukudo;M
• 通讯作者: M

Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients : twice daily versus once daily dosing.

活体肝移植患者的环孢素暴露和钙调神经磷酸酶活性：每日两次与每日一次给药。

• 发表时间: 2006
• 期刊: Liver Transpl 12・2
• 作者: Michihiro Shibata;et. al.;Fukudo M et al.
• 通讯作者: Fukudo M et al.