AASLD 2013:干扰素-α治疗失败NUC治疗先天免疫反应的持续恢复

StephenW

TITLE: Sustained restoration of innate immune responses and sAg decline in sequential NUC therapy following failed Pegylated-Interferon-α therapy in Chronic Hepatitis B
AUTHORS (FIRST NAME, LAST NAME): Upkar S. Gill1, Dimitra Peppa2, Lorenzo Micco2, Graham R. Foster1, Mala K. Maini2, Patrick T. Kennedy1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London, School of Medicine & Dentistry, QMUL, London, United Kingdom.
2. Division of Infection & Immunity, UCL, London, United Kingdom.
ABSTRACT BODY: INTRODUCTION: Treatment strategies in Chronic Hepatitis B (CHB) are rapidly evolving and greater consideration is being given to combination/sequential therapies. Recently a Pegylated-Interferon-α (PEG-IFN-α) switch strategy following viral suppression with a nucleos(t)ide analogue (NUC) was demonstrably superior to NUC monotherapy in sAg reduction and loss. The mechanism underpinning this effect remains ill defined. We have demonstrated boosting of NK cell responses in eAg-negative patients treated with PEG-IFN-α whereas long-term NUC’s have been shown to restore T-cell responses. We tested whether it would be possible to combine these two complementary effects by investigating whether augmented NK cell responses can be maintained on sequential NUC therapy, following PEG-IFN-α failure.

PATIENTS & METHODS: PBMC’s from 18 eAg-positive patients during PEG-IFN-α therapy were utilised. 8/18 patients, considered PEG-IFN-α non-responders after 48 weeks therapy, progressed to sequential NUC therapy and were followed until viral suppression was achieved. Phenotypic and functional analysis of NK cell subsets was performed by multicolour flow cytometry. Changes in immune responses were correlated with simultaneous measurements of ALT, HBV DNA and sAg titres.

RESULTS: PEG-IFN-α treatment expanded the CD56bright NK cell population by a mean of 3-fold (p=0.0001). Expression of the C-type lectin receptors (NKG2A, NKG2C, NKG2D) and natural cytotoxicity receptors (NKp30, NKp44, NKp46) were analysed. A 2-fold increase in NKp30 and a 1.5-fold increase in NKp46 expression on CD56bright NK cells was noted during PEG-IFN-α (p=0.03 and 0.04 respectively), sustained on sequential NUC therapy; whilst no significant change was detected in the C-type lectin receptors or NKp44 expression. An increase in the expression of IFN-γ producing CD56bright NK cells, during PEG-IFN-α therapy (p=0.05) was sustained on sequential NUC therapy; a functional restoration not achieved with NUC’s alone. These changes were associated with a sAg decline of 1.22 logIU/ml from baseline (p=0.05).

CONCLUSIONS: PEG-IFN-α expanded the CD56bright NK cell subset; NK cell expression of NKp30, NKp46 and IFN-γ production was augmented and sustained on sequential NUC therapy, correlating with a greater reduction in sAg levels compared to PEG-IFN-α alone or NUC monotherapy. Thus PEG-IFN-α in non-responders induces sustained innate boosting which is maintained on sequential NUC therapy, in association with sAg decline. Further work is needed to establish whether this priming effect is also present when early PEG-IFN-α stopping rules are applied.

StephenW

简介：治疗慢性乙型肝炎（ CHB ）的策略迅速发展和更大正在考虑组合/序贯疗法。最近，聚乙二醇干扰素α （ PEG - IFN -α）的开关策略，抑制病毒与核苷（酸）类似物（ NUC ）明确优于NUC单药治疗凹陷的减少和消失。支撑这种效果的机制仍然不明确。我们已经证明了提高NK细胞应答EAG负与PEG - IFN-α治疗的患者，而长期的核苷类似物已被证明是T细胞反应还原。我们测试是否有可能结合这两个互补效应，通过调查增强NK细胞的反应是否可以保持顺序NUC治疗后， PEG - IFN-α失败。

患者与方法：外周血单个核细胞的18东亚运动会阳性患者PEG - IFN-α治疗期间已动用。 8/18例， 48周治疗后， PEG - IFN-α无应答者认为，发展顺序NUC治疗并随访，直到达到抑制病毒。 NK细胞亚群的表型和功能分析，进行多色流式细胞仪。免疫反应的变化与ALT ， HBV DNA和凹陷滴度的同时测量。

结果： PEG - IFN-α治疗扩大CD56bright NK细胞种群的平均的3倍（p = 0.0001） 。的C型凝集素受体（ NKG2A ， NKG2C ， NKG2D ）的和自然细胞毒性受体（ NKp30 ， NKp44 ， NKp46 ）中的表达进行了分析。有2倍的增长NKp30和NKp46表达CD56bright NK细胞增加1.5倍PEG -IFN- α （ P = 0.03和0.04 ） ，持续顺序NUC治疗，而没有显着的变化是检测过程中注意到C型凝集素受体NKp44表达。的表达增加IFN-γ的生产CD56bright NK细胞，在PEG - IFN - α治疗（p值= 0.05） ，持续顺序NUC治疗，没有达到与NUC的单独的功能恢复。这些变化与凹陷从基线下降1.22 logIU /毫升（ P = 0.05） 。

结论： PEG - IFN-α的扩大CD56bright NK细胞亚群， NK细胞表达， NKp30 ， NKp46 ， IFN - γ的产生增强和持续的顺序NUC治疗， sAg的水平相比， PEG - IFN-α的更大的减少相关的单独或NUC单药治疗。因此， PEG - IFN-α诱导无应答者与生俱来的持续提高顺序NUC治疗，保持与凹陷下降的。需要进一步的工作，以确定这是否启动效应也是目前PEG - IFN-α月初停止规则的应用。

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