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

(1)肝移植术后复发丙型肝炎患者肝脏中自然杀伤(NK)细胞亚群根据CD56-CD56^(+Bright)和CD56^(+DIM)的细胞表面密度，可将人NK细胞分为两个亚群，每个亚群具有不同的表型。我们研究了活体供肝移植(LDLT)后复发丙型肝炎患者肝脏中NK细胞亚群的变化。同时对慢性丙型肝炎(CHC)患者和LDLT供者进行对照研究。结果显示，复发性丙型肝炎患者肝脏CD56^(+Bright)亚群明显低于慢性丙型肝炎患者和正常献血者。LDLT大鼠肝脏CD56^(+DIM)亚群上的活化标记CD69的表达显著增加。我们的结果表明，进一步检测肝内NK细胞亚群的状态可能为了解丙型肝炎复发的快速进展机制提供新的见解。(2)肝移植后复发丙型肝炎患者肝脏的基因表达谱我们利用肝活检标本研究了LDLT术后复发丙型肝炎患者肝脏中的基因表达谱。(3)慢性丙型肝炎患者干扰素联合利巴韦林治疗前后肝组织中NK和NKT细胞的表达已有研究表明，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丙型肝炎病毒清除中的参与仍然不清楚。我们发现在接受干扰素-a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丙型肝炎病毒清除密切相关。

(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.