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

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-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 7

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Mechanistic studies for plasmid MIP-1α and plasmid Flt3L. (A) BALB/c mic...
Mechanistic studies for plasmid MIP-1α and plasmid Flt3L. (A) BALB/c mice were immunized intramuscularly with sham plasmid, gp120 DNA vaccine alone, gp120 DNA vaccine mixed with plasmid MIP-1α and plasmid Flt3L (delivered equally in both legs), or gp120 DNA vaccine in the left leg (L) and plasmid MIP-1α and plasmid Flt3L in the right leg (R). (B) Mice were immunized with the gp120 DNA vaccine, with or without plasmid MIP-1α and plasmid Flt3L, and received daily i.v. and i.p. injections of saline, 1 μg human MIP-1α protein (hu MIP-1α), or 1 μg murine MIP-1α protein (mu MIP-1α) for 3 days. ND, not done. (C) Mice were immunized with the gp120 DNA vaccine with or without plasmid MIP-1α and plasmid Flt3L at doses of 50 μg, 5 μg, or 0.5 μg of each plasmid in 50-μl injection volumes. (D) Mice were immunized with the gp120 DNA vaccine with or without plasmid MIP-1α and plasmid Flt3L at doses of 50 μg of each plasmid in 50-μl or 15-μl injection volumes. Vaccine-elicited cellular immune responses were assessed by Dd/P18 tetramer binding to CD8+ T lymphocytes on day 10 following immunization.