Development of the lymphocyte-homing modulator against hepatitis

抗肝炎淋巴细胞归巢调节剂的开发

• 批准号: 16590625
• 负责人: KOBAYASHI Eiji
• 金额: $ 2.24万
• 依托单位: JICHI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590625/
• 关键词: Chronic hepatitis; Viral hepatitis; Lymphocyte homing; FTY720; KRP-203; ウイルス性肝炎

T cell-mediated immune responses play a critical role in a variety of liver injuries including autoimmune hepatitis. Injection of concanavalin A (Con A) into mice mimics the histological and pathological phenotype of T cell-mediated hepatitis. Recent advances in host immune control of organ transplantation include the development of sphingosine-1-phosphate (S1P) receptor agonists such as FTY720, which alter lymphocyte homing but do not suppress host general immunity. Herein we examined the effect of the new S1P receptor agonist KRP-203 on the Con A-induced liver damage model. In normal liver lymphocytes of BALB/c mice, both FTY720 and KRP203 promoted lymphocyte sequestering from the liver to secondary lymph nodes and significantly reduced the number of liver lymphocytes (p<0.05). Based on this observation, KRP203 was employed in the Con A-induced hepatitis model. KRP203 markedly reduced the number of CD4^+ lymphocytes that infiltrate Con A-treated liver (p<0.05) and successfully reduced serum transaminase elevation (p=0.017), therefore protecting mice from Con A-induced liver injury. Interestingly this homing modulation less occur in natural hepatic T cell homing through the chemokine receptor, CXCR4. Therefore, S1P receptor agonists preferentially target CXCR4^+CD4^+ peripheral blood T lymphocytes and suppress the occurrence of Con A-induced hepatitis, suggesting their therapeutic usefulness against T cell-mediated hepatic injury.

T 细胞介导的免疫反应在包括自身免疫性肝炎在内的多种肝损伤中发挥着关键作用。将刀豆球蛋白 A (Con A) 注射到小鼠体内可模拟 T 细胞介导的肝炎的组织学和病理表型。器官移植宿主免疫控制的最新进展包括开发 1-磷酸鞘氨醇 (S1P) 受体激动剂，例如 FTY720，它可以改变淋巴细胞归巢，但不会抑制宿主一般免疫。在此，我们研究了新型 S1P 受体激动剂 KRP-203 对 Con A 诱导的肝损伤模型的影响。在BALB/c小鼠的正常肝淋巴细胞中，FTY720和KRP203均促进淋巴细胞从肝脏隔离至次级淋巴结，并显着减少肝淋巴细胞数量（p<0.05）。基于这一观察，KRP203被用于Con A诱导的肝炎模型。 KRP203 显着减少了浸润 Con A 治疗肝脏的 CD4+ 淋巴细胞数量 (p<0.05)，并成功降低血清转氨酶升高 (p=0.017)，从而保护小鼠免受 Con A 诱导的肝损伤。有趣的是，这种归巢调节很少发生在通过趋化因子受体 CXCR4 归巢的天然肝 T 细胞中。因此，S1P受体激动剂优先靶向CXCR4^+CD4^+外周血T淋巴细胞并抑制Con A诱导的肝炎的发生，表明它们对T细胞介导的肝损伤具有治疗作用。

项目成果

免疫抑制剤の進歩

免疫抑制剂的进展

• 发表时间: 2005
• 期刊: 日本臨床 63(11)
• 作者: H.Kita;H.Yamamoto;K.Sugano;et al.;小林 英司
• 通讯作者: 小林 英司

A novel immunomodulator KRP-203 combined with cyclosporine prolonged graft survival and abrogated transplant vasculopathy in rat heart allografts.

新型免疫调节剂 KRP-203 与环孢菌素联合使用可延长大鼠同种异体心脏移植物的存活率并消除移植血管病变。

• 发表时间: 2005
• 期刊: Transplant Proc. 37(1)
• 作者: Takahashi M;et al.
• 通讯作者: et al.

2-アミノ-1,3-プロパン時オール誘導体を有効成分とする肝臓疾患治療剤

以2-氨基-1,3-丙醇衍生物为有效成分的肝病治疗剂

• 发表时间: 2005

Recent progress in immunosuppressive drugs

免疫抑制药物的最新进展

• 发表时间: 2005
• 期刊: Nippon Rinsyou. 63(11)
• 作者: Kobayashi;E.
• 通讯作者: E.

Efficacy of mycrophenolic acid combined with KRP-203, a novel immunomodulator, in a rat heart transplantation model

霉酚酸联合新型免疫调节剂KRP-203在大鼠心脏移植模型中的疗效

• 发表时间: 2006
• 期刊: Journal of Heart and Lung Transplantation 25(3)
• 作者: Suzuki C;et al.
• 通讯作者: et al.