title: Recruitment and expansion of dendritic cells in vivo potentiate the immunogenicity of plasmid DNA vaccines.
abstract: DCs are critical for priming adaptive immune responses to foreign antigens. However, the utility of harnessing these cells in vivo to optimize the immunogenicity of vaccines has not been fully explored. Here we investigate a novel vaccine approach that involves delivering synergistic signals that both recruit and expand DC populations at the site of antigen production. Intramuscular injection of an unadjuvanted HIV-1 envelope (env) DNA vaccine recruited few DCs to the injection site and elicited low-frequency, env-specific immune responses in mice. Coadministration of plasmids encoding the chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) and the DC-specific growth factor fms-like tyrosine kinase 3 ligand with the DNA vaccine resulted in the recruitment, expansion, and activation of large numbers of DCs at the site of inoculation. Consistent with these findings, coadministration of these plasmid cytokines also markedly augmented DNA vaccine---elicited cellular and humoral immune responses and increased protective efficacy against challenge with recombinant vaccinia virus. These data suggest that the availability of mature DCs at the site of inoculation is a critical rate-limiting factor for DNA vaccine immunogenicity. Synergistic recruitment and expansion of DCs in vivo may prove a practical strategy for overcoming this limitation and potentiating immune responses to vaccines as well as other immunotherapeutic strategies.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Sumida
authors.forename: Paul F
authors.initials: PF
authors.lastname: McKay
authors.forename: Diana M
authors.initials: DM
authors.lastname: Truitt
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kishko
authors.forename: Janelle C
authors.initials: JC
authors.lastname: Arthur
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Jackson
authors.forename: Darci A
authors.initials: DA
authors.lastname: Gorgone
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lifton
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D000818:Animals; D019496:Cancer Vaccines; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D004279:DNA, Viral; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D015497:HIV-1 / Q000235:genetics; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000378:metabolism; D013997:Time Factors; D019444:Vaccines, DNA; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D019496:Cancer Vaccines; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D004279:DNA, Viral; D000939:Epitopes; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D019444:Vaccines, DNA; C084881:flt3 ligand protein