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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion.
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Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion.

机译：慢性乙型肝炎抗病毒治疗期间的程序性死亡1表达：乙型肝炎e抗原血清转化的影响。

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Hyperexpression of the programmed death 1 (PD-1) molecule is a hallmark of exhausted T-cells, having a negative impact on T-cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)-positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment-induced viremia reduction and HBeAg seroconversion with respect to PD-1 levels and T-cell reactivity. PD-1 expression was assessed by (1) flow cytometry and (2) quantitative real-time polymerase chain reaction; hepatitis B virus (HBV)-specific CD8+ T-cells were quantitated by pentamer staining; T-cell reactivity to HBV antigens was determined by interferon gamma (IFNgamma) and interleukin 10 (IL-10) enzyme-linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD-1 expression correlated closely with viremia levels. On therapy, PD-1 decreased significantly on total CD8+ T-cells, HBV-specific CD8+T-cells, and CD3+/CD8- T-cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD-1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD-1 decrease with a 50% reduction in the frequency of PD-1+/CD8+ T-cells, which was not observed in patients remaining HBeAg-positive. The decrease in PD-1 expression was associated with increased frequencies of IFNgamma-producing T-cells and decreased frequencies of IL-10 producing T-cells. At baseline, PD-1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD-1 expression and HBcAg-specific effector phenotypes. CONCLUSION: These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD-1 expression and resulting T-cell impairment. Treatment-induced suppression of HBV replication reduces PD-1 expression; however, additional immunotherapeutic interventions are needed for restoration of T-cell functions.
机译：程序性死亡1（PD-1）分子的过度表达是疲惫的T细胞的标志，对T细胞的激活和功能有负面影响。我们纵向研究了18名接受直接抗病毒药（替比夫定或拉米夫定）治疗的乙型肝炎e抗原（HBeAg）阳性患者，以确定就PD-1水平和T细胞反应性而言，治疗引起的病毒血症减少和HBeAg血清转化之间的关系。通过（1）流式细胞仪和（2）定量实时聚合酶链反应评估PD-1的表达;通过五聚体染色对乙型肝炎病毒（HBV）特异性CD8 + T细胞进行定量;通过干扰素γ（IFNgamma）和白介素10（IL-10）酶联免疫吸附斑点（ELISPOT）测定来确定T细胞对HBV抗原的反应性;和中央/效应记忆表型由表型标记定义。 PD-1表达与病毒血症水平密切相关。治疗后，PD-1在总CD8 + T细胞，HBV特异性CD8 + T细胞和CD3 + / CD8- T细胞上均呈阳性细胞百分比（P <0.01）和平均荧光强度显着降低（P <0.05），这与PD-1信使RNA水平显着降低（P = 0.001）相当。 HBeAg血清转化（6/18例患者）导致PD-1进一步降低，PD-1 + / CD8 + T细胞频率降低50％，而在保持HBeAg阳性的患者中未观察到。 PD-1表达的降低与产生IFNγ的T细胞的频率增加和产生IL-10的T细胞的频率降低有关。在基线时，PD-1的表达与乙型肝炎核心抗原（HBcAg）中枢和效应记忆表型的频率直接相关，而在PD-1的表达与HBcAg特异性效应表型之间却呈负相关。结论：这些结果表明，在慢性HBV感染中，病毒血症水平和HBeAg均驱动PD-1表达并导致T细胞损伤。治疗诱导的HBV复制抑制可降低PD-1的表达;然而，需要额外的免疫治疗干预来恢复T细胞功能。

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