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.利用人体组织标本的基因表达谱：检测部分自体肠（n=192）和肝移植（n=208）组织标本中MDR1、CYP3A4、CYP3A5、CYP3A7和CYP3A43的mRNA表达水平和基因多态性。手术时天然小肠中 MDR1 的 mRNA 表达水平是调整他克莫司初始剂量的重要生物标志物。活体肝移植后立即进行的移植肝中 CYP3A5 的单核苷酸多态性 (SNP) 数据与术后天他克莫司的剂量递增显着相关。2.阐明相关的药代动力学和药效学因素。免疫抑制剂的个体差异：手术时MDR1 mRNA表达水平、CYP3A5*3 SNP和移植物与受者体重比以及群体药物动力学分析发现，经典的临床测试标志物具有统计学上显着的固定效应。此外，我们发现基于他克莫司的初始剂量方案，移植后急性细胞排斥的频率成功降低至 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情况，用术后第3、7、14天外周血细胞总RNA分数。使用超过500个点的汇总临床样本，血细胞中MDR1 mRNA高表达的患者他克莫司的目标治疗水平往往较高而不是糖皮质激素受体 (GR/NR3C1)。这些结果表明组织中的各种蛋白质，例如天然小肠和外周白细胞中的 MDR1 mRNA 水平以及 CYP3A5然而，移植肝和自体肠道的基因型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的策略。未来应澄清针对他克莫司的反应。

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

Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient

• DOI: 10.2133/dmpk.21.122
• 发表时间: 2006-01-01
• 期刊: DRUG METABOLISM AND PHARMACOKINETICS
• 影响因子: 2.1
• 作者: Fukatsu, Sachio;Fukudo, Masahide;Inui, Ken-ichi
• 通讯作者: Inui, Ken-ichi

Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients

• DOI: 10.1016/j.transproceed.2005.02.081
• 发表时间: 2005-05-01
• 期刊: TRANSPLANTATION PROCEEDINGS
• 影响因子: 0.9
• 作者: Masuda, S;Goto, M;Inui, K
• 通讯作者: Inui, K

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

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