慢性HBV感染中T细胞功能异常的发病机制及相关治疗方法

StephenW

Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches
Paola Fisicaro  1   2 , Valeria Barili  1   2 , Marzia Rossi  1   2 , Ilaria Montali  1 , Andrea Vecchi  1 , Greta Acerbi  1   2 , Diletta Laccabue  1 , Alessandra Zecca  1 , Amalia Penna  1 , Gabriele Missale  1   2 , Carlo Ferrari  1   2 , Carolina Boni  1
Affiliations
Affiliations

    1
    Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
    2
    Department of Medicine and Surgery, University of Parma, Parma, Italy.

    PMID: 32477347 PMCID: PMC7235343 DOI: 10.3389/fimmu.2020.00849

Abstract

A great effort of research has been devoted in the last few years to developing new anti-HBV therapies of finite duration that also provide effective sustained control of virus replication and antigen production. Among the potential therapeutic strategies, immune-modulation represents a promising option to cure HBV infection and the adaptive immune response is a rational target for novel therapeutic interventions, in consideration of the key role played by T cells in the control of virus infections. HBV-specific T cells are severely dysfunctional in chronic HBV infection as a result of several inhibitory mechanisms which are simultaneously active within the chronically inflamed liver. Indeed, the liver is a tolerogenic organ harboring different non-parenchymal cell populations which can serve as antigen presenting cells (APC) but are poorly efficient in effector T cell priming, with propensity to induce T cell tolerance rather than T cell activation, because of a poor expression of co-stimulatory molecules, up-regulation of the co-inhibitory ligands PD-L1 and PD-L2 upon IFN stimulation, and production of immune regulatory cytokines, such as IL10 and TGF-β. They include resident dendritic cells (DCs), comprising myeloid and plasmacytoid DCs, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs) as well as the hepatocytes themselves. Additional regulatory mechanisms which contribute to T cell attrition in the chronically infected liver are the high levels of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines, the up-regulation of inhibitory checkpoint receptor/ligand pairs, the expansion of regulatory cells, such as CD4+FOXp3+ Treg cells, myeloid-derived suppressor cells and NK cells. This review will deal with the interactions between immune cells and liver environment discussing the different mechanisms which contribute to T cell dysfunction in chronic hepatitis B, some of which are specifically activated in HBV infection and others which are instead common to chronic inflammatory liver diseases in general. Therapeutic interventions targeting dysregulated pathways and cellular functions will be also delineated.

Keywords: T cell exhaustion; chronic HBV infection; immune-therapy; immunoregulatory mechanisms; liver environment.

Copyright © 2020 Fisicaro, Barili, Rossi, Montali, Vecchi, Acerbi, Laccabue, Zecca, Penna, Missale, Ferrari and Boni.

StephenW

慢性HBV感染中T细胞功能异常的发病机制及相关治疗方法
Paola Fisicaro 1 2，瓦莱里亚·巴里利1 2，马尔齐亚·罗西1 2，伊拉里亚·蒙塔利1，安德里亚·韦基1，格雷塔·阿塞比1 2，迪莱塔·拉卡布埃1，亚历山德拉·泽卡1，阿玛莉亚·佩纳1，加布里埃莱·米萨莱1 2，卡洛·法拉利1 2，卡罗莱纳州Boni 1
隶属关系
隶属关系

1个
意大利帕尔马省Azienda Ospedaliero-Universitaria di Parma病毒性免疫病理学实验室，传染病和肝病学部门。
2
意大利帕尔马大学帕尔马大学医学与外科系。

PMID：32477347 PMCID：PMC7235343 DOI：10.3389 / fimmu.2020.00849

抽象

在过去的几年中，已经进行了大量的研究以开发新的有限持续时间的抗-HBV疗法，该疗法还可以有效地持续控制病毒复制和抗原产生。在潜在的治疗策略中，考虑到T细胞在控制病毒感染中的关键作用，免疫调节是治愈HBV感染的有前途的选择，而适应性免疫应答是新型治疗措施的合理目标。 HBV特异性T细胞在慢性HBV感染中严重失调，这是由于几种抑制机制在慢性发炎的肝脏中同时起作用的结果。的确，肝脏是具有不同非实质细胞群的致耐受力器官，可以充当抗原呈递细胞（APC），但在效应T细胞启动方面效率低下，因为它诱导T细胞耐受而不是T细胞活化，原因是共刺激分子表达不佳，在干扰素刺激下共抑制配体PD-L1和PD-L2上调，以及免疫调节细胞因子（如IL10和TGF-β）的产生。它们包括驻留的树突状细胞（DC），组成的髓样和浆细胞样DC，肝窦状内皮细胞（LSEC），库普弗细胞（KC），肝星状细胞（HSC）以及肝细胞本身。导致慢性感染的肝脏中T细胞耗损的其他调控机制是高水平的可溶性介体，如精氨酸酶，吲哚胺2,3-二加氧酶（IDO）和抑制性细胞因子，抑制性检查点受体/配体对的上调，调节细胞的扩增，例如CD4 + FOXp3 + Treg细胞，髓样抑制细胞和NK细胞。这篇综述将探讨免疫细胞与肝脏环境之间的相互作用，并探讨导致慢性乙型肝炎T细胞功能异常的不同机制，其中一些机制在HBV感染中被特异性激活，而另一些则在慢性炎症性肝病中很常见。一般。还应描述针对失调的途径和细胞功能的治疗性干预措施。

关键词：T细胞衰竭慢性HBV感染；免疫疗法免疫调节机制肝脏环境。

版权所有©2020 Fisicaro，Barili，Rossi，Montali，Vecchi，Acerbi，Laccabue，Zecca，Penna，Missale，法拉利和Boni。

StephenW

https://www.frontiersin.org/articles/10.3389/fimmu.2020.00849/pdf