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.