Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release - 16/08/11
Reprint requests: Paola Parronchi, MD, Department Internal Medicine, Section of Immunoallergology, University of Florence, Vle Morgagni 85, 50134 Florence, Italy.Florence, Italy
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-⍺, and IL-6 by CD14+ cells and IFN-⍺ 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.
Le texte complet de cet article est disponible en PDF.Key words : Adjuvants, immunotherapy, heterocycles, Toll-like receptors, allergy, TH1/TH2 lymphocytes, GATA-3, T-box expressed in T cells, nuclear factor κB
Abbreviations used : BDCA, CpG-ODN, DC, NF-κB, PDC, PMA, Poly(I:C), R-848, SA, T-bet, TCL, TLR
Plan
| Supported by funds from the European Community (project QLK3-CT-2002-02026), Associazione Italiana per la Ricerca sul Cancro, and Ministero dell’Università e della Ricerca Scientifica. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 118 - N° 2
P. 511-517 - août 2006 Retour au numéro
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