干扰素α诱导NK细胞响应乙肝病毒载抑制持续变化的一些体内

StephenW

Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo

    Upkar S. Gill,
    Dimitra Peppa,
    Lorenzo Micco,
    Harsimran D. Singh,
    Ivana Carey,
    Graham R. Foster,
    Mala K. Maini ,
    Patrick T. F. Kennedy


PLOS x

    Published: August 3, 2016
    http://dx.doi.org/10.1371/journal.ppat.1005788

   
Abstract

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.
Author Summary

Current therapies for CHB are limited in achieving HBsAg decline and loss leading to a cure. Although PegIFNα may be used, the majority of patients progress to NUC therapy due to treatment failure. PegIFNα and NUCs used in isolation act differentially on the immune response; PegIFNα induces NK cell activation and NUC therapy may partially restore T cell function. Data, however, are limited on the immune effects when these therapies are used in sequence or in combination. Here, we analysed the immune effects of PegIFNα followed by sequential NUC therapy and show this treatment strategy maintains the cumulative expansion of antiviral CD56bright NK cells, following PegIFNα-priming. HBsAg reduction was greater in patients treated with sequential NUCs when compared with de novo NUCs, highlighting the potential benefit of PegIFNα-priming. Such sustained boosting of NK cells on sequential NUCs following PegIFNα-priming has not previously been described, raising the potential of ‘long-lived’ NK cell populations in keeping with their emerging adaptive features. These findings provide a mechanistic and immunological rationale to explore this treatment strategy for CHB whilst awaiting the emergence of new therapies in the field.

StephenW

干扰素α诱导NK细胞响应乙肝病毒载抑制持续变化的一些体内

    Upkar·吉尔，
    迪米特拉佩佩，
    洛伦佐Micco，
    Harsimran D.辛格
    伊万娜·凯莉，
    格雷厄姆R.福斯特，
    麻辣K.迈尼，
    帕特里克·T.·肯尼迪


PLOS点¯x

    发布时间：2016年8月3日
    http://dx.doi.org/10.1371/journal.ppat.1005788

   
抽象

NK细胞是重要的抗病毒效应，在肝脏中高度富集，以调节在持久性病毒感染免疫病理的潜力。在这里，我们检查是否在NK池变化时患者EAG-阳性CHB被“打底”与PegIFNα和重要的是，或诱导的这些变化是否持续进一步切换到核苷（酸）的IDE（顺序NUC治疗后调制长期），目前在临床试验的方法。患者EAG + CHB一个前瞻性招募队列的纵向取样表明，PegIFNα的48周从动CD56bright NK细胞的累积膨胀维持在高于基线水平更高整个后续9个月顺序NUCs的。不料，PegIFNα展开的NK细胞在连续NUCs表现在他们对激活NK细胞受体NKp30和NKP46表达进一步增强。在增生扩展，功能NK细胞以下顺序NUCs比的，只有从头NUCs或PegIFNα治疗的患者相比同伙更加明显。减少朝着CHB的功能治愈的路径循环的HBsAg浓度，一个关键的目标，只是在这些患者在他们的死亡配体TRAIL的表达实现了与增强NK细胞的IFNγ和细胞毒性，但下降。总之，我们的结论是PegIFNα吸可以扩大功能的NK细胞群与由NUCs改变的反应到后续的抗病毒抑制。上具有鲜明的NK细胞的个人资料显示乙肝表面抗原中降幅连续NUCs，对于治疗策略的进一步优化提供机械的见解患者实现持续CHB反应。
笔者总结

慢性乙型肝炎的治疗目前在实现HBsAg的下降和损失导致治愈的限制。虽然可以使用PegIFNα，多数患者进展为NUC治疗因治疗失败。 PegIFNα和在隔离幕使用差分对免疫应答NUCs; PegIFNα诱导NK细胞活化和NUC治疗可部分恢复T细胞功能。数据，但是，只限于对免疫效应时，这些治疗在顺序或组合使用。在这里，我们分析PegIFNα的，然后依次NUC治疗的免疫效果，并表明这一治疗策略保持抗病毒药CD56bright NK细胞，以下PegIFNα吸累计扩张。当与从头NUCs相比，突出PegIFNα吸的潜在益处的HBsAg减少是更大序贯NUCs治疗的患者。这样持续先前没有被描述于下列PegIFNα吸顺序NUCs NK细胞的升压，提高“长寿命”NK细胞群的潜在与新出现的自适应特性一致。这些发现提供了机械和免疫学理探讨CHB这一治疗策略，而等候在现场的新疗法的出现。