title: The nasal dendritic cell-targeting Flt3 ligand as a safe adjuvant elicits effective protection against fatal pneumococcal pneumonia.
abstract: We have previously shown that a pneumococcal surface protein A (PspA)-based vaccine containing DNA plasmid encoding the Flt3 ligand (FL) gene (pFL) as a nasal adjuvant prevented nasal carriage of Streptococcus pneumoniae. In this study, we further investigated the safety and efficacy of this nasal vaccine for the induction of PspA-specific antibody (Ab) responses against lung infection with S. pneumoniae. C57BL/6 mice were nasally immunized with recombinant PspA/Rx1 (rPspA) plus pFL three times at weekly intervals. When dynamic translocation of pFL was initially examined, nasal pFL was taken up by nasal dendritic cells (DCs) and epithelial cells (nECs) but not in the central nervous systems, including olfactory nerve and epithelium. Of importance, nasal pFL induced FL protein synthesis with minimum levels of inflammatory cytokines in the nasal washes (NWs) and bronchoalveolar lavage fluid (BALF). NWs and BALF as well as plasma of mice given nasal rPspA plus pFL contained increased levels of rPspA-specific secretory IgA and IgG Ab responses that were correlated with elevated numbers of CD8(+) and CD11b(+) DCs and interleukin 2 (IL-2)- and IL-4-producing CD4(+) T cells in the nasal mucosa-associated lymphoid tissues (NALT) and cervical lymph nodes (CLNs). The in vivo protection by rPspA-specific Abs was evident in markedly reduced numbers of CFU in the lungs, airway secretions, and blood when mice were nasally challenged with Streptococcus pneumoniae WU2. Our findings show that nasal pFL is a safe and effective mucosal adjuvant for the enhancement of bacterial antigen (Ag) (rPspA)-specific protective immunity through DC-induced Th2-type and IL-2 cytokine responses.
authors.affiliation: Department of Preventive Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kataoka
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Fujihashi
authors.forename: Keita
authors.initials: K
authors.lastname: Oma
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fukuyama
authors.forename: Susan K
authors.initials: SK
authors.lastname: Hollingshead
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sekine
authors.forename: Shigetada
authors.initials: S
authors.lastname: Kawabata
authors.forename: Hiro-O
authors.initials: HO
authors.lastname: Ito
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
authors.forename: Kazunori
authors.initials: K
authors.lastname: Oishi
mesh_terms: D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis* / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D004847:Epithelial Cells / Q000378:metabolism; D007071:Immunoglobulin A, Secretory / Q000096:biosynthesis / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009296:Nasal Cavity / Q000276:immunology; D009297:Nasal Mucosa / Q000276:immunology*; D059085:Nasal Sprays; D010957:Plasmids; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000276:immunology*; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000517:prevention & control; D011994:Recombinant Proteins; D013296:Streptococcus pneumoniae / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; D008565:Membrane Proteins; D059085:Nasal Sprays; D022242:Pneumococcal Vaccines; D011994:Recombinant Proteins; D014614:Vaccines, Synthetic; C084881:flt3 ligand protein; C051592:pneumococcal surface protein A