title: Cytokine-dependent anti-viral role of CD4-positive T cells in therapeutic vaccination against chronic hepatitis B viral infection.
abstract: There are several lines of evidence suggesting that specific vaccine therapy with a standard hepatitis B virus (HBV) vaccination reduces HBV replication. The aim of this study was to investigate the anti-viral mechanism of vaccine therapy in chronic hepatitis B patients. Nineteen patients were assigned to receive either vaccine therapy (n = 13) or no treatment as a control (n = 6). Vaccinated patients were analyzed for T cell proliferative responses specific for envelope antigen and cytokine production by antigen-specific T cells. ELISPOT and cytotoxicity assays also were carried out for limited blood samples. Serum HBV DNA levels decreased significantly at 3 months after completion of therapy and thereafter as compared to the baseline ones, and were significantly lower in vaccinated patients than in controls at 12 and 18 months after completion of therapy. Vaccination induced antigen-specific CD4+ T cell proliferative responses in four patients (30.8%). The production of high levels of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) by antigen-specific T cells was found in six patients (46.0%) who showed significantly lower HBV DNA levels in serum at 6 (P = 0.04) and 18 months (P = 0.005) after completion of therapy than those without high levels of cytokine production. Vaccination did not induce antigen-specific CD8+ T cells or cytotoxic T cells. These results suggest that envelope-specific CD4+ T cells may control directly HBV replication by producing anti-viral cytokines rather than providing help for cytotoxic T cells in therapeutic vaccination against chronic HBV infection.
authors.affiliation: Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Minamikogushi Ube, Yamaguchi 755-8505, Japan.
authors.forename: Fenyu
authors.initials: F
authors.lastname: Ren
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Funatsuki
authors.forename: Akio
authors.initials: A
authors.lastname: Hayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ishiko
authors.forename: Muneko
authors.initials: M
authors.lastname: Furutani
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Korenaga
authors.forename: Satoyoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Tomomi
authors.initials: T
authors.lastname: Konishi
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Okita
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology*; D006801:Humans; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma