RESUMO
TLR agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. The aim of this study was to evaluate the immunostimulatory properties of a novel compound incorporating covalently linked moieties designed to stimulate both TLR2 and TLR7. This dual TLR2/TLR7 agonist induced the maturation of dendritic cells and primed substantial populations of cytolytic and highly polyfunctional effector CD8+ T cells in vitro, and safely potentiated the immunogenic properties of a nanoparticulate Ag in vivo, eliciting humoral responses with a balanced TH1/TH2 profile in mice. Collectively, these data reveal the potential utility of chimeric adjuvants with synergistic activities mediated via TLRs.
Assuntos
Adjuvantes Imunológicos , Imunidade Celular , Imunidade Humoral , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/imunologia , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/imunologia , Animais , Formação de Anticorpos , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Citocinas , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Proteína do Núcleo p24 do HIV/administração & dosagem , Proteína do Núcleo p24 do HIV/imunologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Proteínas Recombinantes de Fusão/imunologia , VacinaçãoRESUMO
We describe novel STING-activating cyclic dinucleotides whose constituent nucleosides are adenosine and inosine and that vary by ribose substitution, internucleotide linkage position, and phosphate modification. In mammalian cells in vitro, some of these cAIMP analogs induce greater STING-dependent IRF and NF-κB pathway signaling than do the reference agonists for murine (DMXAA) or human (2',3'-cGAMP) STING. In human blood ex vivo, they induce type I interferons (IFNs) and proinflammatory cytokines: for the former, 3',3'-cAIMP (9; EC50 of 6.4 µM) and analogs 52-56 (EC50 of 0.4-4.7 µM), which contain one or two 2'-fluoro-2'-deoxyriboses and/or bis-phosphorothioate linkages, are more potent than 2',3'-cGAMP (EC50 of 19.6 µM). Interestingly, 9 induces type I IFNs more strongly than do its linkage isomers 2',3'-cAIMP (10), 3',2'-cAIMP (23), and 2',2'-cAIMP (27). Lastly, some of the cAIMP analogs are more resistant than 2',3'-cGAMP to enzymatic cleavage in vitro. We hope to exploit our findings to develop STING-targeted immunotherapies.
