自然杀伤细胞表型的调制和自然杀伤/ T细胞相互作用的核苷

StephenW

Viral Hepatitis
Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B
Authors

    First published: 29 October 2015Full publication history
    DOI: 10.1002/hep.28155View/save citation
    Cited by: 0 articles Check for new citations
    Article has an altmetric score of 4
    Funding Information

    Potential conflict of interest: Dr. Lampertico consults, advises, and is on the speakers’ bureau for Roche, GlaxoSmithKline, MSD, Bristol-Myers Squibb, and Gilead. Dr. Ferrari consults and received grants from Merck-Schering, Roche, Janssen-Cilag, and Gilead. He consults for Boehringer Ingleheim and Transgene. He received grants from Novartis. Dr. Missale consults for Bayer. Dr. Boni consults for Transgene. Dr. Colombo advises, is on the speakers’ bureau, and received grants from Bristol-Myers Squibb and Gilead. He advises and is on the speakers’ bureau for Roche, Novartis, Bayer, Tibotec, Vertex, Janssen, and AbbVie. He advises Merck, Achillion, and GlaxoSmithKline. He is on the speakers’ bureau for MSD and Sanofi.

    This work was supported by a grant (PRUa1RI-2012-006) from Regione Emilia-Romagna, Italy, Programma di Ricerca Regione-Università 2010-2012, by a grant (2011-0644) from Fondazione Cariplo, Italy, and by a FIRB grant from the Italian Ministry of the University and Research, Protocol RBAP10TPXK.

Abstract

Natural killer (NK) and hepatitis B virus (HBV)-specific T cells are functionally impaired in chronic hepatitis B (CHB). Understanding to what extent nucleos(t)ide analogue (NUC) therapy can improve T- and NK-cell responses is important in the perspective of immunomonitoring strategies for a safe and earlier NUC withdrawal and of novel combination therapies based on modulation of antiviral immunity. To gain further insights into T/NK-cell interplay, we studied NK-cell phenotype and function in hepatitis B e antigen–negative chronic HBV patients either untreated (25) or NUC treated (36 hepatitis B surface antigen [HBsAg]+ and 10 HBsAg–/hepatitis B surface antibody [anti-HBs]+). Interferon-gamma, interleukin-2, and tumor necrosis factor alpha (TNF-α) production by HBV-specific T cells was also analyzed in NUC-treated patients. NK cells from chronic naïve patients showed an “inflammatory” phenotype defined by increased expression of TNF-related apoptosis-inducing ligand (TRAIL), CD38, and Ki67 that significantly declined upon viremia suppression and alanine aminotransferase normalization induced by NUC therapy. Reversion to a quiescent NK-cell phenotype was associated with restoration of the HBV-specific T-cell function. T- and NK-cell responses showed an inverse correlation, with an opposite behavior in individual NUC-treated patients. NK-cell depletion as well as TRAIL and NKG2D pathway blockade induced a significant improvement of the HBV-specific T-cell function. Conclusions: NK cells can express regulatory activity on T cells in NUC-treated patients with prevalent inhibition of CD4 T cells, likely needed to limit persistent T-cell activation. NK-cell phenotype is modulated by NUC therapy and its reversion to quiescence mirrors efficient HBV-specific T-cell responses. Thus, changes of NK-cell phenotype may predict acquisition of antiviral control before anti-HBs seroconversion and represent the groundwork for future studies aimed at assessing whether NK phenotyping can be translated into the clinical practice to guide NUC suspension.(Hepatology 2015;62:1697–1709)

StephenW

病毒性肝炎
自然杀伤细胞表型的调制和自然杀伤/ T细胞相互作用的核苷（酸）类似物IDE治疗乙型肝炎e抗原阴性的慢性乙肝
作者

    首次出版：10月29日2015Full出版物历史
    DOI：10.1002 / hep.28155View /保存引文
    引述：0物品检查新引文
    文章的altmetric比分4比
    资金信息

    的利益冲突：Lampertico医生咨询，建议，并在扬声器的罗氏，葛兰素史克公司，MSD，施贵宝和吉利德局。法拉利医生咨询，并从默克先灵葆雅，罗氏，扬森 - Cilag公司和Gilead公司收到的补助。他咨询了勃林格Ingleheim和转基因。他从诺华公司收到的补助金。 Missale医生咨询拜耳。博尼博士咨询的转基因。科伦坡博士建议，是对扬声器的局，并从施贵宝公司和Gilead公司收到的补助。他建议，是对发言者的罗氏，诺华，拜耳，Tibotec公司，顶点，扬森和艾伯维局。他建议默克，艾琪尔顿，和葛兰素史克。他对说话者的为MSD和赛诺菲局。

    这项工作是由大区艾米利亚 - 罗马涅大区，意大利，PROGRAMMA二RICERCA大区 - UNIVERSITA 2010- 2012年，赠款（PRUa1RI-2012-006），由基金会Cariplo，意大利，补助金（2011-0644），并通过FIRB从授予意大利教育部的大学和研究协议RBAP10TPXK。

抽象

自然杀伤（NK）和乙型肝炎病毒（HBV） - 特异性T细胞在功能上受损慢性乙型肝炎（CHB）。理解到什么程度核苷（酸）类似物IDE（NUC）治疗能提高T细胞和NK细胞的反应是在immunomonitoring策略的基础上抗病毒免疫的调节新的组合疗法安全和更早NUC撤出的角度很重要。为了获得进一步的见解T / NK细胞相互作用，我们研究了NK细胞表型和功能的乙型肝炎e抗原阴性的慢性乙肝患者未处理（25）或NUC治疗（36乙肝表面抗原[HBsAg的] + 10 HBsAg- /乙型肝炎表面抗体[抗HBs] +）。干扰素-γ，白细胞介素-2，肿瘤坏死因子α（TNF-α）生产由HBV特异性T细胞中的NUC治疗的患者进行了分析。从慢性初治患者的NK细胞显示通过肿瘤坏死因子相关凋亡诱导配体（TRAIL）增加的表达所限定的“炎症”的表型，CD38，和Ki67后病毒血症抑制和诱导NUC疗法丙氨酸转氨酶正常化该显著下降。回复到静止NK细胞表型与恢复HBV特异性T细胞功能的相关联。 T-和NK细胞反应呈负相关，与在个人NUC治疗的患者的相对行为。 NK细胞耗尽以及TRAIL与NKG2D通路封锁诱导了显著改善HBV特异性T细胞的功能。结论：NK细胞能表达在NUC治疗的患者与普遍抑制CD4 + T细胞，可能需要限制持续T细胞活化T细胞上调节活性。 NK细胞的表型是由NUC疗法及其逆转调制以静止镜高效HBV特异性T细胞反应。因此，NK细胞表型的变化可以预测采集抗病毒控制的抗HBs血清转换之前和表示了基础为今后的研究，目的是评估的NK表型是否可以被翻译成的临床实践中，引导NUC悬浮液​​（肝脏病2015; 62： 1697年至1709年）