Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo.
Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo.
复制标题
DOI：
10.1371/journal.ppat.1005788
复制
发表时间：
2016-08
期刊：
影响因子：
6.7
通讯作者：
Kennedy PT
中科院分区：
文献类型：
--
作者：
Gill US;Peppa D;Micco L;Singh HD;Carey I;Foster GR;Maini MK;Kennedy PT
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的免疫发病机制的潜力。在这里，我们检查了当eAg阳性CHB患者用PegIFNα“致敏”时是否诱导NK池的变化，重要的是，这些变化是否在转换为核苷（酸）（序贯NUC治疗）后长期持续或进一步调节，这是目前在临床上测试的方法。前瞻性招募的eAg+CHB患者队列的纵向采样显示，在随后9个月的连续NUC中，由48周PegIFNα驱动的CD 56 bright NK细胞累积扩增维持在高于基线水平。出乎意料的是，在连续NUC期间，PegIFNα扩增的NK细胞显示其活化NK细胞受体NKp 30和NKp 46的表达进一步增强。序贯NUC治疗后增殖的功能性NK细胞的扩增比仅接受初治NUC或PegIFNα治疗的患者的比较队列更明显。降低循环HBsAg浓度是CHB功能性治愈的关键目标，仅在NK细胞IFNγ和细胞毒性增强但死亡配体TRAIL表达降低的患者中实现。总之，我们得出结论，PegIFNα引发可以扩增功能性NK细胞群体，其对NUC随后的抗病毒抑制的反应性改变。具有不同NK细胞特征的连续NUC患者显示HBsAg下降，为进一步优化治疗策略以实现CHB的持续应答提供了机制见解。目前CHB的治疗方法在实现HBsAg下降和丢失导致治愈方面受到限制。尽管可以使用PegIFNα，但大多数患者由于治疗失败而进展到NUC治疗。单独使用的PegIFNα和NUC对免疫应答的作用不同; PegIFNα诱导NK细胞活化，NUC治疗可能部分恢复T细胞功能。然而，数据是有限的免疫效果时，这些疗法的顺序或组合使用。在这里，我们分析了PegIFNα随后进行NUC序贯治疗的免疫效应，并显示这种治疗策略在PegIFNα引发后维持了抗病毒CD 56 bright NK细胞的累积扩增。与初治NUC相比，序贯NUC治疗患者的HBsAg下降幅度更大，突出了PegIFNα预激的潜在获益。在PegIFNα引发后，NK细胞在连续NUC上的这种持续增强先前尚未描述，提高了“长寿”NK细胞群体的潜力，与其新兴的适应性特征保持一致。这些发现提供了一个机制和免疫学的理由，探索这种治疗策略的慢性乙型肝炎，同时等待出现新的疗法在该领域。
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. 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.