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Recruitment and expansion of dendritic cells in vivo potentiate the immunogenicity of plasmid DNA vaccines
Shawn M. Sumida, … , Norman L. Letvin, Dan H. Barouch
Shawn M. Sumida, … , Norman L. Letvin, Dan H. Barouch
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1334-1342. https://doi.org/10.1172/JCI22608.
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Article Vaccines

Recruitment and expansion of dendritic cells in vivo potentiate the immunogenicity of plasmid DNA vaccines

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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-1α (MIP-1α) 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

Shawn M. Sumida, Paul F. McKay, Diana M. Truitt, Michael G. Kishko, Janelle C. Arthur, Michael S. Seaman, Shawn S. Jackson, Darci A. Gorgone, Michelle A. Lifton, Norman L. Letvin, Dan H. Barouch

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Figure 4

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Immunogenicity of MIP-1α/Flt3L–augmented DNA vaccines. BALB/c mice (n = ...
Immunogenicity of MIP-1α/Flt3L–augmented DNA vaccines. BALB/c mice (n = 8 per group) were immunized with sham plasmid; the gp120 DNA vaccine alone; or the gp120 DNA vaccine with plasmid Flt3L, plasmid MIP-1α, or the combination of both plasmid cytokines. We injected 50 μg of each plasmid with sufficient sham plasmid to keep the total DNA dose per mouse constant. Vaccine-elicited immune responses were assessed by (A) Dd/P18 tetramer binding to CD8+ T lymphocytes, (B) env-pooled peptide and P18 epitope peptide-specific ELISPOT assays, and (C) gp120-specific ELISAs. The ELISPOT and ELISA assays were performed on day 28 following immunization. SFCs, spot forming cells.
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