title: Dendritic cell-mediated, DNA-based vaccination against hepatitis C induces the multi-epitope-specific response of humanized, HLA transgenic mice.
abstract: Hepatitis C virus (HCV) is the etiologic agent of chronic liver disease, hepatitis C. Spontaneous resolution of viral infection is associated with vigorous HLA class I- and class II-restricted T cell responses to multiple viral epitopes. Unfortunately, only 20% of patients clear infection spontaneously, most develop chronic disease and require therapy. The response to chemotherapy varies, however; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success. Vector-mediated vaccination with multi-epitope-expressing DNA constructs alone or in combination with chemotherapy offers an additional treatment approach. Gene sequences encoding validated HLA-A2- and HLA-DRB1-restricted epitopes were synthesized and cloned into an expression vector. Dendritic cells (DCs) derived from humanized, HLA-A2/DRB1 transgenic (donor) mice were transfected with these multi-epitope-expressing DNA constructs. Recipient HLA-A2/DRB1 mice were vaccinated s.c. with transfected DCs; control mice received non-transfected DCs. Peptide-specific IFN-γ production by splenic T cells obtained at 5 weeks post-immunization was quantified by ELISpot assay; additionally, the production of IL-4, IL-10 and TNF-α were quantified by cytokine bead array. Splenocytes derived from vaccinated HLA-A2/DRB1 transgenic mice exhibited peptide-specific cytokine production to the vast majority of the vaccine-encoded HLA class I- and class II-restricted T cell epitopes. A multi-epitope-based HCV vaccine that targets DCs offers an effective approach to inducing a broad immune response and viral clearance in chronic, HCV-infected patients.
authors.affiliation: Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Bianca J
authors.initials: BJ
authors.lastname: Lavelle
authors.affiliation: Institute for Immunology and Informatics, University of Rhode Island, Providence, Rhode Island, United States of America.
authors.forename: Joe
authors.initials: J
authors.lastname: Desrosiers
authors.affiliation: EpiVax, Inc., Providence, Rhode Island, United States of America.
authors.forename: Matt T
authors.initials: MT
authors.lastname: Ardito
authors.affiliation: EpiVax, Inc., Providence, Rhode Island, United States of America.
authors.forename: Frances
authors.initials: F
authors.lastname: Terry
authors.affiliation: EpiVax, Inc., Providence, Rhode Island, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Martin
authors.affiliation: Institute for Immunology and Informatics, University of Rhode Island, Providence, Rhode Island, United States of America; EpiVax, Inc., Providence, Rhode Island, United States of America.
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
authors.affiliation: Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gregory
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000517:prevention & control*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000235:genetics / Q000276:immunology
chemical_list: D039521:CD11c Antigen; D000939:Epitopes; D015789:HLA-A2 Antigen; D059811:HLA-DRB1 Chains; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D007371:Interferon-gamma
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