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

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
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。
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

随着年龄的增长，乙型肝炎病毒（HBV）可以诱导细胞介导的免疫反应，导致单一治愈或进行性肝损伤。在成人获得性感染中，HBV抗原通常被清除，在婴儿期获得性感染中呈阴性，他们持续存在。因此，在婴儿期间增加的个体代表了慢性感染HBV（CHB）的大多数患者。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。我们证明，协同刺激分子OX40配体免疫细胞的年龄依赖性表达在确定HBV免疫性中是关键的，并且用OX40激动剂治疗导致改善了您的Ng小鼠中的HBV抗原清除，以及增强了年轻T细胞应答的强度小鼠和成年小鼠，它们在年轻时暴露于HBV并形成CHB血清学特征。类似的，在人类中，我们显示肝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