Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues
Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues
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DOI：
10.1053/j.gastro.2012.07.014
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发表时间：
2012-10-01
期刊：
影响因子：
29.4
通讯作者：
Ferrari, Carlo
中科院分区：
文献类型：
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作者：
Boni, Carolina;Laccabue, Diletta;Ferrari, Carlo
背景与目的：慢性乙型肝炎病毒 (HBV) 感染患者中，持续暴露于高浓度抗原会破坏 T 细胞功能。目前尚不清楚核苷类似物长期抑制 HBV 在多大程度上可以恢复抗病毒 T 细胞功能。我们将接受核苷类似物治疗的患者的 HBV 特异性 T 细胞反应与在其他 HBV 控制条件下检测到的反应进行了比较。方法：我们分析了用覆盖整个 HBV 基因型 D 序列的肽刺激 10 天后，以及用选定的 CD8 表位和相应的 HLA-A2 右旋体离体刺激 HBV 特异性 T 细胞中干扰素 γ、白细胞介素 2 和肿瘤坏死因子 α 的细胞内水平。将接受核苷类似物治疗的感染完全控制（HBV DNA 阴性/乙型肝炎表面抗原抗体阳性）或部分控制（HBV DNA 阴性/乙型肝炎表面抗原阳性）的患者的结果与自发或干扰素α诱导急性或慢性感染消退的患者、非活动性 HBV 携带者或 未经治疗的乙型肝炎e抗原阴性的慢性感染患者。结果：虽然感染完全控制的核苷类似物治疗患者的 HBV 特异性 T 细胞在体外功能失调，但在体外扩增后它们具有有效的反应。这些反应与自发缓解急性乙型肝炎病毒感染的患者的反应相当。接受核苷类似物治疗的 HBV DNA 阴性但乙型肝炎表面抗原阳性的患者的 T 细胞反应水平较低，但反应高于未经治疗的慢性感染患者。结论：尽管长期暴露于大量抗原，但长期使用核苷（酸）类似物治疗后，HBV感染受到抑制的患者的T细胞的体外反应性可以恢复。增加抗病毒 T 细胞反应的免疫疗法可能会增加接受长期核苷（酸）类似物治疗的患者完全控制 HBV 的可能性。
BACKGROUND & AIMS: In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t) ide analogues with those detected in other conditions of HBV control. METHODS: We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor alpha in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t) ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections. RESULTS: Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection. CONCLUSIONS: In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.