title: Reduced hepatitis B virus surface antigen-specific Th1 helper cell frequency of chronic HBV carriers is associated with a failure to produce antigen-specific antibodies in the trimera mouse.
abstract: In chronic hepatitis B virus (HBV) infection weak antiviral immune responses are associated with viral persistence. We studied possible immune deficits underlying the lack of serum antibodies of such patients against the HBV surface antigen (HBsAg) in a novel human/mouse chimeric model. A hepatitis B surface antigen (HBs) vaccination of Balb/c mice engrafted with peripheral blood mononuclear cells (PBMC) of naturally HBV-immunized donors induced high frequencies of human HBsAg-specific B and T helper 1 (Th1) cells. These responses were associated with high serum anti-HBs antibody levels of the subclasses immunoglobulin G1 (IgG1) and IgG2 that are driven by interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). In contrast, PBMC of chronic HBV carriers transplanted into the chimera failed to produce anti-HBs antibodies after vaccination with HBsAg and exhibited a deficit of antigen-specific Th1 cells. A possible influence of HBsAg or viremia was excluded by the lack of viral replication in such chimera. The observed T-cell defect was specific for HBsAg, as the B- and T-cell responses to tetanus toxoid (TT) were fully retained. Thus, our study shows that viral persistence in chronic HBV carriers is associated with an HBsAg-specific Th1 cell defect, which likely is responsible for the insufficient neutralizing anti-HBs-antibody response and is not reversed by HBs vaccination. Alternative approaches to induce HBs-specific Th1 cell responses might represent a future therapeutic option.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: W O
authors.initials: WO
authors.lastname: Böcher
authors.forename: E
authors.initials: E
authors.lastname: Galun
authors.forename: H
authors.initials: H
authors.lastname: Marcus
authors.forename: N
authors.initials: N
authors.lastname: Daudi
authors.forename: D
authors.initials: D
authors.lastname: Terkieltaub
authors.forename: D
authors.initials: D
authors.lastname: Shouval
authors.forename: H F
authors.initials: HF
authors.lastname: Löhr
authors.forename: Y
authors.initials: Y
authors.lastname: Reisner
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001782:Blood Donors; D002353:Carrier State / Q000276:immunology*; D002678:Chimera / Q000276:immunology; D000939:Epitopes; D006510:Hepatitis B Antibodies / Q000276:immunology*; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000517:prevention & control; D006801:Humans; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000637:transplantation; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D000939:Epitopes; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens