无环核苷磷酸盐在乙型肝炎病毒感染治疗中的免疫调节机制

StephenW

Hepatology. 2019 Sep 17. doi: 10.1002/hep.30956. [Epub ahead of print]
Immunomodulatory mechanism of acyclic nucleoside phosphates in treatment of hepatitis B virus infection.
Murata K1,2, Tsukuda S3,4, Suizu F5, Kimura A6, Sugiyama M2, Watashi K4, Noguchi M5, Mizokami M2.
Author information

1
    Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Nasushiobara, Japan.
2
    Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.
3
    RIKEN Center for integrative Medical Sciences (IMS), Wako, Japan.
4
    Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
5
    Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
6
    Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan.

Abstract

Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic and novel therapies are desired. It has been believed that all NUCs have similar function to inhibit HBV reverse-transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)-λ3 in the gastrointestinal tract suggests that ANPs are not only distinct in their structures but also in their functions from nucleoside analogs (lamivudine and entecavir). Since enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS-mediated cytokine profile in PBMCs. This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS-mediated interleukin (IL)-10 production, which reciprocally induced IL-12p70 and tumor necrosis factor-α production in a dose-dependent manner. Furthermore, the combination of IFN-α and ANPs synergistically enhanced LPS-mediated IL-12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS-mediated IL-10 production. CONCLUSIONS: Only ANPs among NUCs have an additional pharmacological effect modulating LPS-mediated cytokine productions, which expect favorable immune responses towards HBV elimination. This additional immunomodulation by ANPs in PBMCs, as well as IFN-λ3 induction in the gastrointestinal tract, provides novel insights on HBV treatment.

© 2019 by the American Association for the Study of Liver Diseases.
KEYWORDS:

CD14+monocytes; IL-10; cytokines; mTOR; nucleos(t)ide analogs

PMID:
    31529730
DOI:
    10.1002/hep.30956

StephenW

肝病。 2019年9月17日.doi：10.1002 / hep.30956。 [Epub提前发布]
无环核苷磷酸盐在乙型肝炎病毒感染治疗中的免疫调节机制。
村田K1,2，Tsukuda S3,4，Suizu F5，Kimura A6，Sugiyama M2，Watashi K4，Noguchi M5，Mizokami M2。
作者信息

1
    国际卫生与福利大学医学研究生院消化内科，日本那须盐原市。
2
    日本市川国立全球健康与医学中心基因组医学科学项目。
3
    日本和光市理研综合医学科学中心（IMS）。
4
    日本东京国立传染病研究所病毒学系II。
五
    日本北海道大学北海道大学遗传医学研究所癌症生物学系。
6
    日本市川市国立全球健康与医学中心研究所肝炎与免疫学研究中心免疫与病理学系。

抽象

目前使用核苷酸类似物（NUCs）的治疗可以安全地控制乙型肝炎病毒（HBV）的复制并改善HBV患者的预后。然而，不能完全清除HBV是有问题的，并且需要新的疗法。已经认为所有NUC具有相似的抑制HBV逆转录酶的功能。然而，我们最近的研究结果表明，只有无环核苷膦酸盐（ANPs;阿德福韦酯和替诺福韦地索普西富马酸盐）在胃肠道中诱导干扰素（IFN）-λ3具有额外的作用，这表明ANPs不仅在结构上有明显的差异，而且在它们的结构中也是如此。核苷类似物（拉米夫定和恩替卡韦）的功能。由于肠溶性脂多糖（LPS）可以穿过肠道并影响外周血单核细胞（PBMC），因此我们假设口服ANP可以进一步调节PBMC中LPS介导的细胞因子谱。这项研究表明，使用ANP预处理健康志愿者或HBV患者的PBMC可以抑制LPS介导的白介素（IL）-10的产生，从而以剂量依赖的方式相互诱导IL-12p70和肿瘤坏死因子-α的产生。此外，IFN-α和ANP的组合可协同增强PBMC中LPS介导的IL-12p70的产生。机理分析表明，ANPs的细胞代谢产物直接结合Akt蛋白，抑制其向质膜的转运，从而损害Akt磷酸化。因此，用ANP对PBMC进行预处理会损害LPS介导的IL-10的产生。结论：仅NUC中的ANP具有调节LPS介导的细胞因子产生的额外药理作用，其预期对消除HBV具有有利的免疫反应。 PBMC中ANP的这种额外免疫调节以及胃肠道中的IFN-λ3诱导，为HBV治疗提供了新的见解。

©2019美国肝病研究协会。
关键词：

CD14 +单核细胞; IL-10;细胞因子; mTOR的;核苷（酸）类似物

结论：
    31529730
DOI：
    10.1002 / hep.30956