Gill Upkar S, Peppa Dimitra, Micco Lorenzo, Singh Harsimran D, Carey Ivana, Foster Graham R, Maini Mala K, Kennedy Patrick T F
Hepatology, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, London, United Kingdom.
Department of Hepatology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.
PLoS Pathog. 2016 Aug 3;12(8):e1005788. doi: 10.1371/journal.ppat.1005788. eCollection 2016 Aug.
NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg-positive CHB are 'primed' with PegIFNα and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48-weeks of PegIFNα was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Unexpectedly, PegIFNα-expanded NK cells showed further augmentation in their expression of the activating NK cell receptors NKp30 and NKp46 during sequential NUCs. The expansion in proliferating, functional NK cells was more pronounced following sequential NUCs than in comparison cohorts of patients treated with de novo NUCs or PegIFNα only. Reduction in circulating HBsAg concentrations, a key goal in the path towards functional cure of CHB, was only achieved in those patients with enhancement of NK cell IFNγ and cytotoxicity but decrease in their expression of the death ligand TRAIL. In summary, we conclude that PegIFNα priming can expand a population of functional NK cells with an altered responsiveness to subsequent antiviral suppression by NUCs. Patients on sequential NUCs with a distinct NK cell profile show a decline in HBsAg, providing mechanistic insights for the further optimisation of treatment strategies to achieve sustained responses in CHB.
自然杀伤细胞（NK细胞）是重要的抗病毒效应细胞，在肝脏中高度富集，具有调节持续性病毒感染免疫发病机制的潜力。在此，我们研究了e抗原阳性慢性乙型肝炎（CHB）患者接受聚乙二醇化干扰素α（PegIFNα）“启动”时，NK细胞库是否会发生变化，以及重要的是，在转换为核苷（酸）类药物（序贯核苷类药物治疗）后，这些变化是否会长期持续或进一步受到调节，这是目前正在临床中测试的一种方法。对前瞻性招募的e抗原阳性CHB患者队列进行纵向采样显示，由48周PegIFNα驱动的CD56bright NK细胞的累积扩增在随后9个月的序贯核苷类药物治疗期间维持在高于基线水平。出乎意料的是，在序贯核苷类药物治疗期间，PegIFNα扩增的NK细胞在活化NK细胞受体NKp30和NKp46的表达上进一步增加。与仅接受初治核苷类药物或PegIFNα治疗的患者比较队列相比，序贯核苷类药物治疗后增殖性、功能性NK细胞的扩增更为明显。循环中乙肝表面抗原（HBsAg）浓度降低是CHB功能性治愈道路上的一个关键目标，只有在那些NK细胞干扰素γ（IFNγ）和细胞毒性增强但死亡配体肿瘤坏死因子相关凋亡诱导配体（TRAIL）表达降低的患者中才能实现。总之，我们得出结论，PegIFNα启动可扩增一群功能性NK细胞，其对随后核苷类药物抗病毒抑制的反应性发生改变。接受序贯核苷类药物治疗且具有独特NK细胞谱的患者HBsAg下降，为进一步优化治疗策略以实现CHB持续应答提供了机制性见解。
