难治性慢性丙型肝炎患者抗病毒治疗中NK细胞和Treg细胞的动态变化

Changes in NK cells and regulatory T cells among patients with refractory chronic hepatitis C during antiviral treatment

目的：观察难治性慢性丙型肝炎的NK细胞和Treg细胞动态变化，分析与抗病毒疗效相关的免疫因素。方法采用开放性、前瞻性临床队列研究。入组2009年9月-2010年10月收治的难治性慢性丙型肝炎患者41例（初治组30例和无应答组11例）和健康对照（HC）者11例，初治组给予聚乙二醇干扰素（PEG-IFN）α-2a 180μg/周联合利巴韦林10．6～15 mg·kg-1·d-1治疗48周，无应答组给予PEG-IFNα-2a 180μg/周联合利巴韦林15 mg·kg-1·d-1治疗72周；动态留取细胞和血清，进行HCV RNA、肝功能和NK细胞和Treg细胞的检测，分析与疗效相关的免疫因素。计量资料采用t检验或秩和检验，计数资料采用χ2检验。结果所有患者均完成抗病毒治疗和24周随访，初治获得SVR者17例（56．7％），未获得SVR（nSVR）者13例；无应答组获得SVR者3例（27．2％），未获得SVR（RFP）者为8例（72．7％）。基线总体患者的NK细胞频率低于HC 组，Treg细胞频率高于HC组；同时抗病毒治疗疗程中，初治获得SVR者24周NK细胞频率较基线和4周明显增加，Treg细胞频率较基线和4周明显下降；同时初治nSVR者Treg细胞频率24周时较基线和4周明显升高；无应答组再治疗仍未获得SVR者无论NK细胞频率或者Treg细胞频率均未见明显变化。结论 NK细胞频率的降低以及Treg细胞频率的增加与HCV慢性感染有关；抗病毒治疗后NK细胞及Treg细胞的动态变化，可以预测抗病毒疗效：疗程中NK细胞频率的增加以及Treg细胞频率的下降与疗效好有关。

Objective To investigate the changes in NK cells and regulatory T （Treg）cells among patients with refractory chronic hepatitis C （CHC）during antiviral therapy and to analyze antiviral effect-related immunological factors.Methods A total of 41 patients with refractory CHC （30 treatment-naive patients and 1 1 treatment-unresponsive patients）and 1 1 healthy controls （HC）were enrolled in this prospective open cohort study.Naive patients received pegylated interferon α-2a （Peg-IFN-α-2a）180 μg/week and ribavirin （RBV）10.6 -15 mg/kg/day for 48 weeks,while unresponsive patients received Peg-IFN-α-2a 180 μg/week and RBV 15 mg/kg/day for 72 weeks.Blood cells and serum were dynamically collected to measure HCV RNA,liver function,NK cells and Treg cells and to analyze curative effect-relat-ed immunological factors.Continuous variables were analyzed by t-test or rank sum test,and discrete variables were analyzed by chi-square test.Results All patients finished antiviral treatment and 24-week follow-up survey.Seventeen naive patients （56.7%）and 3 unrespons-ive patients （27.2%）achieved a sustained virologic response （SVR）.The 8 unresponsive patients without SVR were named response-free patients（RFP）.At baseline,the percentage of NK cells in patients was lower than that in the HC group,while the percentage of Treg cells in patients was higher than that in the HC group.During antiviral therapy,in naive patients with SVR,the percentage of NK cells increased at week 24 of treatment,as compared with the baseline and week 4,and the percentage of Treg cells decreased at week 24,as compared with the baseline and week 4;In naive patients without SVR,the percentage of Treg cells increased at week 24,as compared with the baseline and week 4;no significant change in the percentage of NK cells or Treg cells was observed in unresponsive patients without SVR.Conclusion Decrease in NK cells and increase in Treg cells are related to chronic HCV infection.Dynamic changes in NK cells and Treg cells can predict the efficacy of antiviral therapy：the increase in NK cells and decrease in Treg cells,which are indicative of upregulation immune function and downregulation of immunosuppression,can be used for predicting SVR.