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

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Abstract

Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Clinical implications

Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders.

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