title: A new synthetic TLR4 agonist, GLA, allows dendritic cells targeted with antigen to elicit Th1 T-cell immunity in vivo.
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.
authors: Laboratory of Cellular Physiology and Immunology and Chris Browne Center, Rockefeller University, New York, NY 10065-6399, USA.
authors: Austin
authors: A
authors: Pantel
authors: Cheolho
authors: C
authors: Cheong
authors: Durga
authors: D
authors: Dandamudi
authors: Elina
authors: E
authors: Shrestha
authors: Saurabh
authors: S
authors: Mehandru
authors: Luke
authors: L
authors: Brane
authors: Darren
authors: D
authors: Ruane
authors: Angela
authors: A
authors: Teixeira
authors: Leonia
authors: L
authors: Bozzacco
authors: Ralph M
authors: RM
authors: Steinman
authors: M Paula
authors: MP
authors: Longhi
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D006678:HIV / Q000276:immunology; D016655:HIV Core Protein p24 / Q000276:immunology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D016655:HIV Core Protein p24; D008050:Lipid A; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D022223:Vaccines, Subunit; C048988:GLA 27