免疫不足导致 NAs 治疗的慢性乙型肝炎患者转为 Peg-IFN-ɑ 的

StephenW

免疫不足导致 NAs 治疗的慢性乙型肝炎患者转为 Peg-IFN-ɑ 的病毒学突破
大黄1、魏明2、韩美芳3、魏源3、王鹏3、陈玉英3、万小阳3、罗小平4、吴迪5、秦宁6
隶属关系
隶属关系

    1
    华中科技大学同济医学院附属同济医院传染病研究所，武汉 430030电子地址：[email protected]。
    2
    华中科技大学同济医学院附属同济医院传染病研究所，武汉 430030电子地址：[email protected]。
    3
    华中科技大学同济医学院附属同济医院传染病研究所，武汉 430030
    4
    华中科技大学同济医学院附属同济医院儿科，武汉 430030
    5
    华中科技大学同济医学院附属同济医院传染病研究所，武汉 430030电子地址：[email protected]。
    6
    华中科技大学同济医学院附属同济医院传染病研究所，武汉 430030电子邮箱：[email protected]。

    PMID：34848218 DOI：10.1016/j.antiviral.2021.105220

抽象的

背景：慢性乙型肝炎（CHB）患者在从核苷（酸）类似物（NAs）转换为聚乙二醇化干扰素α（Peg-IFN-ɑ）后可能发生病毒学突破（VBT）。本研究旨在表征 VBT 的临床和免疫学特征。

方法：在转换为 Peg-IFN-ɑ 的 NAs 治疗患者中，在外周血和肝活检标本中检查了先天性和适应性免疫细胞的比例。检查了 IFN-ɑ 对单核细胞上 toll 样受体 2 (TLR2) 和程序性细胞死亡配体 1 (PDL1) 表达的体外影响，检查了 CD8+T 细胞上的程序性细胞死亡 1 (PD1)。外周血单核细胞 (PBMC) 用 TLR2 激动剂和/或 PDL1 阻断剂处理，以评估它们对 HBV 复制的影响。

结VBT患者在外周血NA停止后Peg-IFN-ɑ治疗的早期阶段，TLR2+单核细胞比例较低，PD1+HBV特异性CD8+T细胞比例增加，TLR2+CD68+巨噬细胞较少，但更多肝组织中的PDL1+CD68+巨噬细胞和PD1+CD8+T细胞。同时使用 TLR2 激动剂和 PDL1 体外阻断通过促进细胞因子的产生和 CD8+T 细胞的细胞毒性来抑制 HBV 复制。在体外 IFN-ɑ 刺激下，PDL1+单核细胞和 PD1+CD8+T 细胞上调，而 TLR2+单核细胞在分离自 HBeAg 阳性患者或具有高 HBcrAg 滴度的 PBMC 中没有增加。

结论：在 NAs 治疗的患者中，转为 Peg-IFN-ɑ 治疗后，较低的 TLR2+单核细胞和增加的 PD1+HBV 特异性 CD8+T 细胞比例可能有助于 VBT。这种免疫力不足可能与 HBeAg 状态和 HBcrAg 水平有关。

关键词：CHB；免疫反应; Peg-IFN-ɑ;病毒学突破。

版权所有 © 2021。Elsevier B.V. 出版

StephenW

Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg-IFN-ɑ
Da Huang  1 , Weiming Yan  2 , Meifang Han  3 , Wei Yuan  3 , Peng Wang  3 , Yuying Chen  3 , Xiaoyang Wan  3 , Xiaoping Luo  4 , Di Wu  5 , Qin Ning  6
Affiliations
Affiliations

    1
    Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: [email protected].
    2
    Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: [email protected].
    3
    Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
    4
    Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
    5
    Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: [email protected].
    6
    Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: [email protected].

    PMID: 34848218 DOI: 10.1016/j.antiviral.2021.105220

Abstract

Background: Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alfa (Peg-IFN-ɑ). This study aimed to characterize the clinical and immunological features of VBT.

Methods: In NAs-treated patients switching to Peg-IFN-ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8+T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication.

Results: 33 of 166 patients switching to Peg-IFN-ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2+monocyte and increased PD1+HBV-specific CD8+T cell during the early phase of Peg-IFN-ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2+CD68+macrophages but more PDL1+CD68+macrophages and PD1+CD8+T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8+T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1+monocytes and PD1+CD8+T cells were upregulated, whereas TLR2+monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers.

Conclusions: In NAs-treated patients, lower TLR2+monocyte and increased PD1+HBV-specific CD8+T cell proportions potentially contribute to VBT after switching to Peg-IFN-ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.

Keywords: CHB; Immune response; Peg–IFN–ɑ; Virologic breakthrough.

Copyright © 2021. Published by Elsevier B.V.