Research ArticleHEPATITIS

An OX40/OX40L interaction directs successful immunity to hepatitis B virus

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Science Translational Medicine  21 Mar 2018:
Vol. 10, Issue 433, eaah5766
DOI: 10.1126/scitranslmed.aah5766

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Hepatitis immunity: Better with age

Hepatitis B virus (HBV) infection can have severe complications, including cirrhosis and cancer. Most chronic HBV patients are infected at an early age, as adults can readily clear the virus. Publicover et al. used a mouse model of age-dependent HBV clearance and samples from patients to study the mechanisms leading to effective immunity in adults. They discovered that OX40 ligand expression in hepatic immune cells increases with age and is important for viral control. These results clarify some of the chronological differences in the immune response and also suggest that boosting OX40 activity in infants and chronically-infected adults could promote effective HBV immunity.

Abstract

Depending 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.

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