Analysis of the innate immune responses in the liver of patients with chronic hepatitis C following liver transplantation to develop a novel immunotherapy for the recurrent hepatitis C infection

分析肝移植后慢性丙型肝炎患者肝脏的先天免疫反应，以开发针对复发性丙型肝炎感染的新型免疫疗法

• 批准号: 18590723
• 负责人: YAMAGIWA Satoshi
• 金额: $ 2.51万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590723/
• 关键词: transplantation immunology; liver transplantation; natural killer cells; chronic hepatitis C; 移植・再生医療; 免疫学; 臨床

(1) Natural killer (NK) cell subsets in the liver of patients with recurrent hepatitis C following liver transplantationHuman NK cells can be divided into two subsets based on their cell-surface density of CD56 - CD56^(+bright) and CD56^(+dim) - each with distinct phenotypic properties. We investigated the NK cell subsets in the liver of patients with recurrent hepatitis C following living-donor liver transplantation (LDLT). The patients with chronic hepatitis C (CHC) and the donors for LDLT were also investigated as controls. We revealed that the CD56^(+bright) subset was significantly decreased in the liver of patients with recurrent hepatitis C than that in the patients with CHC and the normal donors. The expression of an activation marker CD69 on the CD56^(+dim) subset was significantly increased in the liver of LDLT. Our results suggest that further examination of the status of intrahepatic NK cell subsets might provide a new insight into the mechanism of rapid progression of recurrent hepatitis C infection.(2) Gene expression profiles in the liver of patients with recurrent hepatitis C following liver transplantationWe investigated the gene expression profiles in the liver of patients with recurrent hepatitis C after LDLT using liver biopsy samples. However, we could not find any significant changes in the gene expression profiles among the recurrent hepatitis C patients and CHC patients yet.(3) NK and NKT cells in the liver of patients with chronic hepatitis C before and after interferon plus ribavirin therapyPrevious studies have revealed that functional impairment of NK and NKT cells might be associated with the persistence of hepatitis C virus (HCV). However, the involvement of these cells, which predominate in the liver, in therapeutic HCV clearance is still unclear. We found a close relationship between the significant increase of intrahepatic NK/NKT cells and sustained HCV clearance in CHC patients treated with interferon-a plus ribavirin therapy.

(1)肝移植后复发性丙型肝炎患者肝脏中的自然杀伤（NK）细胞亚群人类NK细胞可根据其CD 56的细胞表面密度分为两个亚群-CD 56 ^（+bright）和CD 56 ^（+dim）-各自具有不同的表型特性。我们研究了活体肝移植（LDLT）后复发性丙型肝炎患者肝脏中的NK细胞亚群。并以慢性丙型肝炎（CHC）患者和LDLT供者作为对照。结果表明，复发性丙型肝炎患者肝组织中CD 56 ^（+bright）亚群明显低于慢性丙型肝炎患者和正常人。LDLT组肝脏中CD 56 ^（+dim）亚群上的活化标志物CD 69的表达显著增加。我们的研究结果表明，进一步检查肝内NK细胞亚群的状态可能会提供一个新的见解复发性丙型肝炎感染的快速进展的机制。(2)肝移植后复发性丙型肝炎患者肝脏中的基因表达谱我们使用肝活检样本研究了LDLT后复发性丙型肝炎患者肝脏中的基因表达谱。但在复发的丙型肝炎患者和慢性丙型肝炎患者中，我们尚未发现任何明显的基因表达谱变化。(3)慢性丙型肝炎患者干扰素联合利巴韦林治疗前后肝脏NK和NKT细胞的变化研究发现，NK和NKT细胞功能受损可能与丙型肝炎病毒（HCV）的持续存在有关。然而，这些在肝脏中占主导地位的细胞在治疗性HCV清除中的参与仍不清楚。我们发现，在接受干扰素-α联合利巴韦林治疗的慢性丙型肝炎患者中，肝内NK/NKT细胞的显著增加与持续的HCV清除之间存在密切关系。

项目成果

【診断ピットフォール 症例から学ぶ】消化器 かゆみ

【诊断误区案例学习】胃肠道瘙痒

• 发表时间: 2007
• 期刊: 内科 99(6)
• 作者: 山際 訓;他
• 通讯作者: 他

PBC病態における自然免疫の関与

先天免疫参与 PBC 病理学

• 发表时间: 2006
• 期刊: 肝胆膵 52(4)
• 作者: 山際 訓;他
• 通讯作者: 他

An inhibitor of c-Jun NK2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins

c-Jun NK2 末端激酶抑制剂 SP600125 通过调节 BH3 蛋白，保护小鼠免受 D-半乳糖胺/脂多糖诱导的肝衰竭

• 发表时间: 2007
• 期刊: Life Science 80(14)
• 作者: Takamura M;et. al.
• 通讯作者: et. al.

Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma

• DOI: 10.1016/j.jhep.2006.01.036
• 发表时间: 2006-08-01
• 期刊: JOURNAL OF HEPATOLOGY
• 影响因子: 25.7
• 作者: Yang, Xiu Hua;Yamagiwa, Satoshi;Aoyagi, Yutaka
• 通讯作者: Aoyagi, Yutaka

Temporal treatment with interferon-beta prevents hepatocellular carcinoma in hepatitis B virus X gene transgenic mice.

• DOI: 10.1016/j.jhep.2007.09.012
• 发表时间: 2008-02
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: K. Yamazaki;Kenta Suzuki;S. Ohkoshi;M. Yano;So Kurita;Y. Aoki;K. Toba;M. Takamura;S. Yamagiwa;Y. Matsuda;Y. Aoyagi