OX40 / OX40L相互作用指导对乙型肝炎病毒的成功免疫力。

StephenW

Sci Transl Med. 2018 Mar 21;10(433). pii: eaah5766. doi: 10.1126/scitranslmed.aah5766.
An OX40/OX40L interaction directs successful immunity to hepatitis B virus.Publicover J1,2, Gaggar A1,2, Jespersen JM1,2, Halac U1,2, Johnson AJ1,2, Goodsell A1,2, Avanesyan L3,4, Nishimura SL5, Holdorf M6, Mansfield KG7, Judge JB7, Koshti A6, Croft M8, Wakil AE3,4, Rosenthal P2,9,10, Pai E1,2, Cooper S2,3,4, Baron JL11,2.
Author information
1Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.2UCSF Liver Center, UCSF, San Francisco, CA 94143, USA.3Liver Immunology Laboratory, California Pacific Medical Center Research Institute, San Francisco, CA 94115, USA.4Division of General and Transplant Hepatology, California Pacific Medical Center Research Institute, San Francisco, CA 94115, USA.5Department of Pathology, UCSF, San Francisco, CA 94143, USA.6Novartis Institute for Biomedical Research, Emeryville, CA 94619, USA.7Discovery and Investigative Pathology, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.8La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.9Department of Pediatrics, UCSF, San Francisco, CA 94143, USA.10Department of Surgery, UCSF, San Francisco, CA 94143, USA.11Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA. [email protected].

AbstractDepending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator. Using an age-dependent mouse model of HBV clearance and persistence in conjunction with human blood and liver tissue, we studied mechanisms of viral clearance to identify new therapeutic targets. We demonstrate that age-dependent expression of the costimulatory molecule OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to improved HBV antigen clearance in young mice, as well as increased strength of T cell responses in young mice and adult mice that were exposed to HBV when they were young and developed a CHB serological profile. Similarly, in humans, we show that hepatic OX40L transcript expression is age-dependent and that increased OX40 expression on peripheral CD4+ T cells in adults is associated with HBV clearance. These findings provide new mechanistic understanding of the immune pathways and cells necessary for HBV immunity and identify potential therapeutic targets for resolving CHB.


PMID:29563320DOI:10.1126/scitranslmed.aah5766

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StephenW

Sci Transl Med。 2018年3月21日; 10（433）。 pii：eaah5766。 doi：10.1126 / scitranslmed.aah5766。
OX40 / OX40L相互作用指导对乙型肝炎病毒的成功免疫力。
公开J1,2，Gaggar A1,2，Jespersen JM1,2，Halac U1,2，Johnson AJ1,2，Goodsell A1,2，Avanesyan L3,4，Nishimura SL5，Holdorf M6，Mansfield KG7，Judge JB7，Kosht​​i A6， Croft M8，Wakil AE3,4，Rosenthal P2,9,10，Pai E1,2，Cooper S2,3,4，Baron JL11,2。
作者信息

1
    美国加州大学旧金山分校医学系（UCSF），旧金山，CA 94143，美国。
2
    UCSF肝脏中心，UCSF，旧金山，CA 94143，美国。
3
    肝脏免疫学实验室，加州太平洋医疗中心研究所，旧金山，加利福尼亚94115，美国。
4
    加利福尼亚太平洋医疗中心研究所普通与移植肝病科，加利福尼亚州旧金山94115，美国。
五
    加利福尼亚大学旧金山分校病理学系，加州94143，美国。
6
    诺华生物医学研究所，Emeryville，CA 94619，USA。
7
    发现和调查病理学，诺华生物医学研究所，剑桥，马萨诸塞州02139，美国。
8
    拉霍亚过敏和免疫学研究所，9420 Athena Circle，La Jolla，CA 92037，美国。
9
    加利福尼亚大学旧金山分校儿科系，加利福尼亚州旧金山94143。
10
    美国加利福尼亚州圣弗朗西斯科94143，加州大学旧金山分校外科。
11
    加利福尼亚大学旧金山分校医学系（UCSF），旧金山，加利福尼亚州94143，美国。 [email protected]。

抽象

取决于采集年龄，乙型肝炎病毒（HBV）可以诱导细胞介导的免疫应答，从而导致治愈或进行性肝损伤。在成人获得性感染中，HBV抗原通常会被清除，而在婴儿期获得性感染中，它们会持续存在。因此，在婴儿期感染的个体代表了大部分慢性感染HBV（CHB）的患者。在大多数CHB患者中可以促进病毒抗原清除的疗法尚未开发出来，并且将代表主要的医疗保健进步和成本缓解。我们使用年龄依赖性的HBV清除率和持续性的小鼠模型结合人体血液和肝脏组织，研究了病毒清除的机制以确定新的治疗靶点。我们证明，肝脏先天免疫细胞对共刺激分子OX40配体（OX40L）的年龄依赖性表达是决定HBV免疫力的关键，并且用OX40激动剂治疗导致年轻小鼠中HBV抗原清除率的提高，以及增强的T细胞反应的年轻小鼠和成年小鼠接触乙肝病毒时，他们年轻，并制定了CHB血清学概况。类似地，在人类中，我们显示肝脏OX40L转录物表达是年龄依赖性的，并且成年人外周CD4 + T细胞上OX40表达增加与HBV清除有关。这些发现为HBV免疫所需的免疫通路和细胞提供了新的机制理解，并确定了解决CHB的潜在治疗靶点。

结论：
    29563320
DOI：
    10.1126 / scitranslmed.aah5766
Sci Transl Med. 2018 Nián 3 yuè 21 rì; 10(433). Pii:Eaah5766. Doi:10.1126/ Scitranslmed.Aah5766.
OX40/ OX40L xiānghù zuòyòng zhǐdǎo duì yǐ xíng gānyán bìngdú dí chénggōng miǎnyì lì.
Gōngkāi J1,2,Gaggar A1,2,Jespersen JM1,2,Halac U1,2,Johnson AJ1,2,Goodsell A1,2,Avanesyan L3,4,Nishimura SL5,Holdorf M6,Mansfield KG7,Judge JB7,Kosht​​i A6, Croft M8,Wakil AE3,4,Rosenthal P2,9,10,Pai E1,2,Cooper S2,3,4,Baron JL11,2.
Zuòzhě xìnxī

1
    měiguó jiāzhōu dàxué jiùjīnshān fēnxiào yīxué xì (UCSF), jiùjīnshān,CA 94143, měiguó.
2
    UCSF gānzàng zhōngxīn,UCSF, jiùjīnshān,CA 94143, měiguó.
3
    Gānzàng miǎnyì xué shíyàn shì, jiāzhōu tàipíngyáng yīliáo zhōngxīn yánjiū suǒ, jiùjīnshān, jiālìfúníyǎ 94115, měiguó.
4
    Jiālìfúníyǎ tàipíngyáng yīliáo zhōngxīn yánjiū suǒ pǔtōng yǔ yízhí gānbìng kē, jiālìfúníyǎ zhōu jiùjīnshān 94115, měiguó.
Wǔ
    jiālìfúníyǎ dàxué jiùjīnshān fēnxiào bìng lǐxué xì, jiāzhōu 94143, měiguó.
6
    Nuòhuá shēngwù yīxué yánjiū suǒ,Emeryville,CA 94619,USA.
7
    Fāxiàn hé diàochá bìng lǐxué, nuòhuá shēngwù yīxué yánjiū suǒ, jiànqiáo, mǎsàzhūsāi zhōu 02139, měiguó.
8
    Lā huò yà guòmǐn hé miǎnyì xué yánjiū suǒ,9420 Athena Circle,La Jolla,CA 92037, měiguó.
9
    Jiālìfúníyǎ dàxué jiùjīnshān fēnxiào érkē xì, jiālìfúníyǎ zhōu jiùjīnshān 94143.
10
    Měiguó jiālìfúníyǎ zhōu shèng fúlǎngxīsī kē 94143, jiāzhōu dàxué jiùjīnshān fēnxiào wàikē.
11
    Jiālìfúníyǎ dàxué jiùjīnshān fēnxiào yīxué xì (UCSF), jiùjīnshān, jiālìfúníyǎ zhōu 94143, měiguó. [email protected].

Chōuxiàng

qǔjué yú cǎijí niánlíng, yǐ xíng gānyán bìngdú (HBV) kěyǐ yòudǎo xìbāo jiè dǎo de miǎnyì yìngdá, cóng'ér dǎozhì zhìyù huò jìnxíng xìng gān sǔnshāng. Zài chéngrén huòdé xìng gǎnrǎn zhōng,HBV kàngyuán tōngcháng huì bèi qīngchú, ér zài yīng'ér qī huòdé xìng gǎnrǎn zhōng, tāmen huì chíxù cúnzài. Yīncǐ, zài yīng'ér qī gǎnrǎn de gètǐ dàibiǎole dà bùfèn mànxìng gǎnrǎn HBV(CHB) de huànzhě. Zài dà duōshù CHB huànzhě zhōng kěyǐ cùjìn bìngdú kàngyuán qīngchú de liáofǎ shàngwèi kāifā chūlái, bìngqiě jiāng dàibiǎo zhǔyào de yīliáo bǎojiàn jìnbù hé chéngběn huǎnjiě. Wǒmen shǐyòng niánlíng yīlài xìng de HBV qīngchú lǜ hé chíxù xìng de xiǎo shǔ móxíng jiéhé réntǐ xiěyè hé gānzàng zǔzhī, yánjiūle bìngdú qīngchú de jīzhì yǐ quèdìng xīn de zhìliáo bǎ diǎn. Wǒmen zhèngmíng, gānzàng xiāntiān miǎnyì xìbāo duì gòng cìjī fēnzǐ OX40 pèi tǐ (OX40L) de niánlíng yīlài xìng biǎodá shì juédìng HBV miǎnyì lì de guānjiàn, bìngqiě yòng OX40 jīdòng jì zhìliáo dǎozhì niánqīng xiǎo shǔ zhōng HBV kàngyuán qīngchú lǜ de tígāo, yǐjí zēngqiáng de T xìbāo fǎnyìng de niánqīng xiǎo shǔ hé chéngnián xiǎo shǔ jiēchù yǐgān bìngdú shí, tāmen niánqīng, bìng zhìdìngle CHB xiěqīng xué gàikuàng. Lèisì de, zài rénlèi zhōng, wǒmen xiǎnshì gānzàng OX40L zhuǎnlù wù biǎodá shì niánlíng yīlài xìng de, bìngqiě chéngnián rén wàizhōu CD4 + T xìbāo shàng OX40 biǎodá zēngjiā yǔ HBV qīngchú yǒuguān. Zhèxiē fāxiàn wèi HBV miǎnyì suǒ xū de miǎnyì tōnglù hé xìbāo tígōngle xīn de jīzhì lǐjiě, bìng què dìng liǎo jiějué CHB de qiánzài zhìliáo bǎ diǎn.

Jiélùn:
    29563320
DOI:
    10.1126/ Scitranslmed.Aah5766