Retention of CD4+ CD25+ FoxP3+ Regulatory T Cells in the Liver after Therapy-Induced Hepatitis C Virus Eradication in Humans
Retention of CD4+ CD25+ FoxP3+ Regulatory T Cells in the Liver after Therapy-Induced Hepatitis C Virus Eradication in Humans
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DOI：
10.1128/jvi.02551-10
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发表时间：
2011-06-01
影响因子：
5.4
通讯作者：
Boonstra, Andre
中科院分区：
文献类型：
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作者：
Claassen, Mark A. A.;de Knegt, Robert J.;Boonstra, Andre
感染丙型肝炎病毒后，在大多数情况下，免疫无法根除病毒，导致感染丙型肝炎病毒的肝脏免疫病理进展缓慢。我们首次通过采集不同时间点的肝脏活检样本，检测了慢性丙型肝炎患者(慢性丙型肝炎患者)在抗病毒治疗期间和治疗后的肝内T细胞和CD4(+)CD25(+)FoxP3(+)调节性T细胞(Treg)。我们发现，在大约50%的慢性丙型肝炎患者中，给予α干扰素和利巴韦林后，肝内Treg的频率增加，这表明在抗病毒治疗期间，Treg对肝内免疫的调节更强。在停止抗病毒治疗后，在成功清除病毒的绝大多数人的肝脏中，肝内Treg的频率保持在基线以上。在治疗诱导清除丙型肝炎病毒RNA几个月后，保留在肝脏中的Treg的表型表明效应器记忆细胞的贡献减少。我们通过多次肝脏采样收集的发现表明，慢性丙型肝炎患者成功的抗病毒治疗并不会导致局部免疫反应正常化，使其恢复到与健康肝脏相当的静息状态。大量Treg的持续存在，其表型反映了相对较弱的抑制活性，表明正在进行免疫病理学的残余调节。这些发现为了解丙型肝炎病毒免疫反应的动态以及治疗对肝内免疫的影响提供了重要的洞察力。
Following infection with the hepatitis C virus (HCV), in most cases immunity fails to eradicate the virus, resulting in slowly progressing immunopathology in the HCV-infected liver. We are the first to examine intrahepatic T cells and CD4(+) CD25(+) FoxP3(+) regulatory T cells (Treg) in patients chronically infected with HCV (chronic HCV patients) during and after antiviral therapy by collecting multiple aspiration biopsy samples from the liver at different time points. We found that intrahepatic Treg frequencies were increased upon alpha interferon and ribavirin administration in about 50% of chronic HCV patients, suggesting stronger regulation of intrahepatic immunity by Treg during antiviral therapy. After cessation of antiviral therapy, the frequency of intrahepatic Treg remained above baseline in the large majority of livers of individuals who successfully cleared the virus. The phenotype of those Treg that were retained in the liver months after therapy-induced clearance of HCV RNA indicated a reduced contribution of effector memory cells. Our findings, gathered by multiple samplings of the liver, indicate that successful antiviral therapy of chronic HCV patients does not lead to normalization of the local immune response to a resting state comparable to that for healthy livers. The continuous presence of high numbers of Treg, with a phenotype reflecting a relatively weak suppressive activity, suggests ongoing residual regulation of immunopathology. These findings provide important insight into the dynamics of the immune response to HCV, as well as the effect of therapy on intrahepatic immunity.