Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release.
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 T(H)2 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-alpha, and IL-6 by CD14(+) cells and IFN-alpha and CXCL10 by blood dendritic cell antigen (BDCA)-4(+) plasmacytoid dendritic cells. A nuclear factor kappaB-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 T(H)2 cells toward the T(H)1/T(H)0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors.


CONCLUSIONS
Critical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific T(H)2 cells to a T(H)1/T(H)0 phenotype.


CONCLUSIONS
Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders.
Filì
Lucia
L
DENOthe Center for Research, Transfer and High Education, University of Florence, Via Morgagni 85, 50134 Florence, Italy.
Ferri
Simona
S
Guarna
Francesco
F
Sampognaro
Salvatore
S
Manuelli
Cinzia
C
Liotta
Francesco
F
Cosmi
Lorenzo
L
Matucci
Andrea
A
Vultaggio
Alessandra
A
Annunziato
Francesco
F
Maggi
Enrico
E
Guarna
Antonio
A
Romagnani
Sergio
S
Parronchi
Paola
P
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000485:Allergens / Q000276:immunology; D000658:Amoxicillin / Q000276:immunology; D039741:Antigens, Dermatophagoides / Q000276:immunology; D060829:Arthropod Proteins; D002460:Cell Line; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000485:Allergens; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D016207:Cytokines; D012333:RNA, Messenger; D051199:Toll-Like Receptor 7; D000658:Amoxicillin; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1; D000225:Adenine