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Eur J Immunol. 2012 Jan;42(1):101-9. doi: 10.1002/eji.201141855. Epub 2011 Dec 12.

A new synthetic TLR4 agonist, GLA, allows dendritic cells targeted with antigen to elicit Th1 T-cell immunity in vivo.

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  • 1Laboratory of Cellular Physiology and Immunology and Chris Browne Center, Rockefeller University, New York, NY 10065-6399, USA.

Abstract

Protein-based vaccines offer safety and cost advantages but require adjuvants to induce immunity. Here we examined the adjuvant capacity of glucopyranosyl lipid A (GLA), a new synthetic non-toxic analogue of lipopolysaccharide. In mice, in comparison with non-formulated LPS and monophosphoryl lipid A, formulated GLA induced higher antibody titers and generated Type 1 T-cell responses to HIV gag-p24 protein in spleen and lymph nodes, which was dependent on TLR4 expression. Immunization was greatly improved by targeting HIV gag p24 to DCs with an antibody to DEC-205, a DC receptor for antigen uptake and processing. Subcutaneous immunization induced antigen-specific T-cell responses in the intestinal lamina propria. Immunity did not develop in mice transiently depleted of DCs. To understand how GLA works, we studied DCs directly from vaccinated mice. Within 4 h, GLA caused DCs to upregulate CD86 and CD40 and produce cytokines including IL-12p70 in vivo. Importantly, DCs removed from mice 4 h after vaccination became immunogenic, capable of inducing T-cell immunity upon injection into naïve mice. These data indicate that a synthetic and clinically feasible TLR4 agonist rapidly stimulates full maturation of DCs in vivo, allowing for adaptive immunity to develop many weeks to months later.

Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID:
22002164
[PubMed - indexed for MEDLINE]
PMCID:
PMC3517108
Free PMC Article

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