title: Development of cell-based tuberculosis vaccines: genetically modified dendritic cell vaccine is a much more potent activator of CD4 and CD8 T cells than peptide- or protein-loaded counterparts.
abstract: Genetically modified dendritic cell (DC)-based vaccines have not been explored for immunization against tuberculosis. A gene-modified DC vaccine expressing Mycobacterium tuberculosis (M.tb) antigen 85A (Ag85A) was developed by using a recombinant replication-deficient adenoviral gene transfer vector (AdAg85A). AdAg85A-transduced DC vaccine (AdAg85/DC) expressed higher levels of IL-12 and was much more immunogenic than Ag85 protein-loaded (pro/DC) or CD4/CD8 T cell peptide-loaded (pep/DC) DC vaccines. Compared to pro/DC or pep/DC, AdAg85/DC elicited a remarkably higher level of ex vivo IFN-gamma production by CD4 and CD8 T cells at weeks 2, 6, and 12 postimmunization, which was coupled with higher frequencies of antigen-specific T cells. By an in vivo CD8 or CD4 T cell cytotoxicity (CTL) assay, AdAg85/DC was shown to provoke much higher and more sustained levels of CD8 and CD4 CTL activity up to 12 weeks postimmunization. Intramuscular (im) AdAg85/DC immunization was more potent than the iv route of AdAg85/DC immunization. Such stronger immunogenicity of im AdAg85/DC vaccination was corroborated with better protection from M.tb challenge. Our results thus suggest that genetically modified DC-based TB vaccine is superior to subunit DC vaccines and has the potential for therapeutic applications.
authors.affiliation: Department of Pathology and Molecular Medicine and Division of Infectious Diseases, Centre for Gene Therapeutics, McMaster University, Hamilton, ON, Canada L8N 3Z5.
authors.forename: Janet I
authors.initials: JI
authors.lastname: Malowany
authors.forename: Sarah
authors.initials: S
authors.lastname: McCormick
authors.forename: Michael
authors.initials: M
authors.lastname: Santosuosso
authors.forename: Xizhong
authors.initials: X
authors.lastname: Zhang
authors.forename: Naoko
authors.initials: N
authors.lastname: Aoki
authors.forename: Patricia
authors.initials: P
authors.lastname: Ngai
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Jaina
authors.initials: J
authors.lastname: Leitch
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bramson
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wan
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013997:Time Factors; D014161:Transduction, Genetic; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D032581:Tuberculosis Vaccines; D014614:Vaccines, Synthetic; D007371:Interferon-gamma