title: Specificity and efficacy of dendritic cell-based vaccination against tuberculosis with complex mycobacterial antigens in a mouse model.
abstract: Dendritic cells (DC) likely play important and unique roles in the generation of protective immunity to mycobacteria. In order to clarify their contributions, bone marrow-derived DC loaded with Mycobacterium tuberculosis sonicate antigens were used to stimulate T cell proliferation both in vitro and in vivo and to vaccinate C57BL/6 mice against subsequent challenge with virulent mycobacteria. Antigen-pulsed DC developed in fetal calf serum (FCS-DC), but not DC developed in normal mouse serum (NMS-DC), stimulated significant proliferation of both naïve and immune T cells in vitro. The difference between cell populations developed in FCS and NMS in the content of CD11c(+) cells and in production of key cytokines indicated that NMS is less supportive for the development of activated DC. However, following adoptive transfer of a single dose of antigen-pulsed DC into naive recipients, NMS-DC induced T cells that proliferated in response to mycobacterial antigen, whereas FCS-DC stimulated strong non-specific proliferation. Vaccination with two doses of antigen-pulsed NMS-DC by the subcutaneous route induced significant protection against intravenous challenge with a moderate dose of virulent M. tuberculosis. DC-vaccinated mice exhibited significant reductions in bacillary loads in the lungs and spleens, and markedly reduced lung pathology. Three doses of antigen-pulsed NMS-DC induced a significant increase in survival time following high dose challenge, which correlated with a significant increase in IFN-gamma-producing cells in both lung and lymphoid tissues, as assessed by the ELISPOT assay. Taken together, these results indicate that DC play a critical role in the induction of protective resistance against virulent mycobacterial challenge accompanied by the development of antigen-reactive, IFN-gamma-producing T cells, and that their antigenic specificity is influenced by the culture conditions under which the DC are developed.
authors.affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Yauza alley, 2, Moscow 107564, Russia.
authors.forename: Elvira
authors.initials: E
authors.lastname: Rubakova
authors.forename: Svetlana
authors.initials: S
authors.lastname: Petrovskaya
authors.forename: Alexander
authors.initials: A
authors.lastname: Pichugin
authors.forename: Valentine
authors.initials: V
authors.lastname: Khlebnikov
authors.forename: David
authors.initials: D
authors.lastname: McMurray
authors.forename: Elena
authors.initials: E
authors.lastname: Kondratieva
authors.forename: Irina
authors.initials: I
authors.lastname: Baturina
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kondratieva
authors.forename: Alexander
authors.initials: A
authors.lastname: Apt
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology; D002417:Cattle; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D003470:Culture Media; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005312:Fetal Blood / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010641:Phenotype; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D013601:T-Lymphocytes / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology / Q000627:therapeutic use*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000942:Antigens, Bacterial; D039521:CD11c Antigen; D003470:Culture Media; D016207:Cytokines; D000939:Epitopes; D032581:Tuberculosis Vaccines