慢性乙型肝炎的体外多酚治疗对HBV特异性CD8 T细胞的功能重建

StephenW

Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B
Acerbi Greta  1 , Montali Ilaria  1 , Ferrigno Gennaro Domenico  1 , Barili Valeria  1 , Schivazappa Simona  2 , Alfieri Arianna  2 , Laccabue Diletta  1 , Loglio Alessandro  3 , Marta Borghi  3 , Massari Marco  4 , Rossi Marzia  1 , Vecchi Andrea  1 , Penna Amalia  2 , Boni Carolina  2 , Missale Gabriele  5 , Lampertico Pietro  3 , Del Rio Daniele  6 , Ferrari Carlo  7 , Fisicaro Paola  5
Affiliations
Affiliations

    1
    Department of Medicine and Surgery, University of Parma, Parma, Italy.
    2
    Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
    3
    1(st) Division of Gastroenterology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy.
    4
    Unit of Infectious Diseases, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
    5
    Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
    6
    Department of Food & Drugs, University of Parma, Parma, Italy.
    7
    Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. Electronic address: [email protected].

    PMID: 33188902 DOI: 10.1016/j.jhep.2020.10.034

Abstract

Background and aims: In chronic HBV infection, exhausted HBV-specific CD8 T cells express misregulated mitochondrion and proteasome functions. To better characterize the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion we analyzed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to target simultaneously both mitochondrial and proteostasis functions were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in chronic HBV patients.

Methods: Lysosome-mediated degradation pathways were analyzed by flow cytometry in virus-specific CD8 T cells from chronic HBV patients, in comparison to patients able to resolve spontaneously HBV infection and healthy subjects. Mitochondrial function, intracellular proteostasis and cytokine production were evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol and oleuropein and their metabolites, either alone or in combination with other bioactive compounds.

Results: HBV-specific CD8 T cells of chronic patients showed impaired autophagic flux. A significant improvement of mitochondrial, proteostasis and antiviral CD8 functions was elicited by resveratrol and oleuropein. Cytokine production was also enhanced by synthetic metabolites which correspond to those generated by resveratrol and oleuropein metabolism in vivo, suggesting that these polyphenols may display their effect also after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalizing effect of mt-antioxidants and of PD-1/PD-L1 blockade.

Conclusion: Targeting simultaneously multiple altered intracellular pathways with the combination of mitochondria-antioxidants and natural polyphenols may represent a promising strategy in the perspective of novel immune reconstitution therapies to treat chronic HBV infection.

Keywords: Chronic HBV infection; T cell functional reconstitution; oleuropein; proteostasis; resveratrol.

Copyright © 2020. Published by Elsevier B.V.

StephenW

慢性乙型肝炎的体外多酚治疗对HBV特异性CD8 T细胞的功能重建
Acerbi Greta 1，Montali Ilaria 1，Ferrigno Gennaro Domenico 1，Barili Valeria 1，Schivazappa Simona 2，Alfieri Arianna 2，Laccabue Diletta 1，Loglio Alessandro 3，Marta Borghi 3，Massari Marco 4，Rossi Marzia 1，Vecchi Andrea 1，Penna阿玛莉亚2号（Amalia 2），卡罗莱纳州2号（Boni Carolina），米萨尔·加布里埃（Missale Gabriele）5号，兰佩蒂科·皮耶特罗（Lampertico Pietro）3号，德尔里约·丹尼尔（Del Rio Daniele）6号，法拉利·卡洛（Ferrari Carlo 7），菲斯卡罗·保罗（Fisicaro Paola）5
隶属关系
隶属关系

    1个
    意大利帕尔马大学帕尔马大学医学与外科系。
    2
    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。
    3
    米兰大学OCCS基金会胃肠病学分会第1届会议，意大利米兰大学奥格德·马焦雷·波利里尼科（Ospedale Maggiore Policlinico）。
    4
    意大利雷焦艾米利亚，雷焦艾米利亚，Azienda USL-IRCCS di传染病科。
    5
    意大利帕尔马大学帕尔马大学医学与外科系；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。
    6
    意大利帕尔马大学帕尔马大学食品与药物系。
    7
    意大利帕尔马大学帕尔马大学医学与外科系；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。电子地址：[email protected]。

    PMID：33188902 DOI：10.1016 / j.jhep.2020.10.034

抽象

背景与目的：在慢性HBV感染中，精疲力竭的HBV特异性CD8 T细胞表达失调的线粒体和蛋白酶体功能。为了更好地表征失调的蛋白质降解机制在T细胞衰竭中的潜在参与，我们分析了HBV特异性CD8 T细胞中的溶酶体介导的自噬。测试了能够同时靶向线粒体和蛋白稳定功能的生物活性化合物，以鉴定最佳组合策略，以重构慢性HBV患者的有效抗病毒CD8 T细胞应答。

方法：与能够自发解决HBV感染的患者和健康受试者相比，通过流式细胞术分析了慢性HBV患者的病毒特异性CD8 T细胞的溶酶体介导的降解途径。在存在或不存在多酚白藜芦醇和橄榄苦苷及其代谢产物的情况下，单独或与其他生物活性化合物联合使用时，在HBV肽刺激的T细胞培养中评估线粒体功能，细胞内蛋白稳态和细胞因子的产生。

结果：慢性患者的HBV特异性CD8 T细胞显示自噬通量受损。白藜芦醇和橄榄苦苷可引起线粒体，蛋白稳定和抗病毒CD8功能的显着改善。与体内白藜芦醇和橄榄苦苷代谢产生的代谢产物相对应的合成代谢产物也能提高细胞因子的产生，这表明这些多酚在体内转化后也可能发挥作用。此外，多酚化合物改善了mt抗氧化剂和PD-1 / PD-L1阻断的T细胞恢复活力。

结论：结合线粒体抗氧化剂和天然多酚同时靶向多种改变的细胞内途径，从治疗慢性乙肝病毒感染的新型免疫重建疗法的角度看，可能是一种有前途的策略。

关键词：慢性HBV感染； T细胞功能重建；橄榄苦苷蛋白质稳态白藜芦醇。

版权所有©2020。由Elsevier B.V.发布。