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Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release

2006; Elsevier BV; Volume: 118; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2006.05.027

1097-6825

Lucia Filì, Simona Ferri, Francesco Guarna, Salvatore Sampognaro, Cinzia Manuelli, Francesco Liotta, Lorenzo Cosmi, Andrea Matucci, Alessandra Vultaggio, Francesco Annunziato, Enrico Maggi, Antonio Guarna, Sergio Romagnani, Paola Parronchi,

Asthma and respiratory diseases

BackgroundNatural or synthetic ligands of Toll-like receptors (TLRs), such as CpG-containing oligodeoxynucleotides and imidazoquinolines, affect the functional phenotype of antigen-specific human T lymphocytes by inducing cytokine release by cells of the innate immunity.ObjectiveIn vitro investigation of the ability of substitute adenines (SAs) to affect antigen-presenting cells and shift the functional phenotype of specific human TH2 cells was performed.MethodsThe functional profile of hapten- and allergen-specific T-cell lines obtained in the absence or presence of modified adenines was assessed by means of quantitative real-time PCR, flow cytometry, and ELISAs. Activation of TLRs was evaluated by means of nucleofection of HEK293 cells.ResultsThe synthetic heterocycle, chemically related to adenine with substitution in positions 2-, 8-, and 9- (SA-2), but not its related derivative lacking 2- and 8- substitutions, stimulated the production of high amounts of IL-12, IL-10, TNF-α, and IL-6 by CD14+ cells and IFN-α and CXCL10 by blood dendritic cell antigen (BDCA)-4+ plasmacytoid dendritic cells. A nuclear factor κB–dependent signaling pathway mediated by SA-2 ligation of TLR7 was responsible for these effects. SA-2 also redirected the in vitro differentiation of either Dermatophagoides pteronyssinus group 1 or amoxicillin-specific TH2 cells toward the TH1/TH0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors.ConclusionCritical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific TH2 cells to a TH1/TH0 phenotype.Clinical implicationsAppropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders. Natural or synthetic ligands of Toll-like receptors (TLRs), such as CpG-containing oligodeoxynucleotides and imidazoquinolines, affect the functional phenotype of antigen-specific human T lymphocytes by inducing cytokine release by cells of the innate immunity. In vitro investigation of the ability of substitute adenines (SAs) to affect antigen-presenting cells and shift the functional phenotype of specific human TH2 cells was performed. The functional profile of hapten- and allergen-specific T-cell lines obtained in the absence or presence of modified adenines was assessed by means of quantitative real-time PCR, flow cytometry, and ELISAs. Activation of TLRs was evaluated by means of nucleofection of HEK293 cells. The synthetic heterocycle, chemically related to adenine with substitution in positions 2-, 8-, and 9- (SA-2), but not its related derivative lacking 2- and 8- substitutions, stimulated the production of high amounts of IL-12, IL-10, TNF-α, and IL-6 by CD14+ cells and IFN-α and CXCL10 by blood dendritic cell antigen (BDCA)-4+ plasmacytoid dendritic cells. A nuclear factor κB–dependent signaling pathway mediated by SA-2 ligation of TLR7 was responsible for these effects. SA-2 also redirected the in vitro differentiation of either Dermatophagoides pteronyssinus group 1 or amoxicillin-specific TH2 cells toward the TH1/TH0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors. Critical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific TH2 cells to a TH1/TH0 phenotype.