Publicover, Jean, Gaggar, Anuj, Jespersen, Jillian, Halac, Ugar, Johnson, Audra, Goodsell, Amanda, Avanesyan, Lia, Nishimura, Stephen, Holdorf, Meghan, Mansfield, Keith, Judge, Joyce, Croft, Michael, Wakil, Adil, Rosenthal, Philip, Pai, Eric, Cooper, Stewart and Baron, Jody (2018) An OX40/OX40L interaction directs successful immunity to hepatitis B virus. Science Translational Medicine, 10 (433). ISSN 1946-62341946-6242

Abstract

Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results either in cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared whereas in infancy 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 demarcate a major healthcare 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 OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to HBV-antigen clearance in young mice, and increased strength of T cell responses in both young mice, and adult mice that were exposed to HBV when they were young and developed a chronic HBV 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 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.

Item Type:	Article
Date Deposited:	05 Apr 2018 00:45
Last Modified:	05 Apr 2018 00:45
URI:	https://oak.novartis.com/id/eprint/34783