title: Enhanced immunogenicity of a tricomponent mannan tetanus toxoid conjugate vaccine targeted to dendritic cells via Dectin-1 by incorporating β-glucan.
abstract: In a previous attempt to generate a protective vaccine against Candida albicans, a β-mannan tetanus toxoid conjugate showed poor immunogenicity in mice. To improve the specific activation toward the fungal pathogen, we aimed to target Dectin-1, a pattern-recognition receptor expressed on monocytes, macrophages, and dendritic cells. Laminarin, a β-glucan ligand of Dectin-1, was incorporated into the original β-mannan tetanus toxoid conjugate providing a tricomponent conjugate vaccine. A macrophage cell line expressing Dectin-1 was employed to show binding and activation of Dectin-1 signal transduction pathway by the β-glucan-containing vaccine. Ligand binding to Dectin-1 resulted in the following: 1) activation of Src family kinases and Syk revealed by their recruitment and phosphorylation in the vicinity of bound conjugate and 2) translocation of NF-κB to the nucleus. Treatment of immature bone marrow-derived dendritic cells (BMDCs) with tricomponent or control vaccine confirmed that the β-glucan-containing vaccine exerted its enhanced activity by virtue of dendritic cell targeting and uptake. Immature primary cells stimulated by the tricomponent vaccine, but not the β-mannan tetanus toxoid vaccine, showed activation of BMDCs. Moreover, treated BMDCs secreted increased levels of several cytokines, including TGF-β and IL-6, which are known activators of Th17 cells. Immunization of mice with the novel type of vaccine resulted in improved immune response manifested by high titers of Ab recognizing C. albicans β-mannan Ag. Vaccine containing laminarin also affected distribution of IgG subclasses, showing that vaccine targeting to Dectin-1 receptor can benefit from augmentation and immunomodulation of the immune response.
authors.affiliation: Department of Chemistry, Alberta Glycomics Centre, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lipinski
authors.forename: Amira
authors.initials: A
authors.lastname: Fitieh
authors.forename: Joëlle
authors.initials: J
authors.lastname: St Pierre
authors.forename: Hanne L
authors.initials: HL
authors.lastname: Ostergaard
authors.forename: David R
authors.initials: DR
authors.lastname: Bundle
authors.forename: Nicolas
authors.initials: N
authors.lastname: Touret
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005936:Glucans; D037181:Lectins, C-Type / Q000008:administration & dosage* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011134:Polysaccharides / Q000276:immunology / Q000378:metabolism; D013745:Tetanus Toxoid / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D014312:Trisaccharides / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D047071:beta-Glucans / Q000276:immunology / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D000939:Epitopes; D005936:Glucans; D037181:Lectins, C-Type; D011134:Polysaccharides; D013745:Tetanus Toxoid; D014312:Trisaccharides; D018074:Vaccines, Conjugate; D047071:beta-Glucans; D000099181:Dectin-1; C008247:laminaran