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

• Published in: Journal of allergy and clinical immunology Vol. 118; no. 2; pp. 511 - 517
• Main Authors: FILL, Lucia, FERRI, Simona, MAGGI, Enrico, GUARNA, Antonio, ROMAGNANI, Sergio, PARRONCHI, Paola, GUARNA, Francesco, SAMPOGNARO, Salvatore, MANUELLI, Cinzia, LIOTTA, Francesco, COSMI, Lorenzo, MATUCCI, Andrea, VULTAGGIO, Alessandra, ANNUNZIATO, Francesco
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 01.08.2006; Elsevier Limited
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Adjuvants, Immunologic - pharmacology; Allergens - immunology; Allergies; Amoxicillin - immunology; Antigens, Dermatophagoides - immunology; Arthropod Proteins; Biological and medical sciences; Cell Line; Cells, Cultured; Chemokines; Cloning; Cysteine Endopeptidases; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Dendritic Cells - drug effects; Dendritic Cells - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - drug effects; Genotype & phenotype; Humans; Hypersensitivity - immunology; Immune system; Immunopathology; Kinases; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Ligands; Lymphocytes; Medical sciences; RNA, Messenger - metabolism; Th2 Cells - immunology; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 7 - metabolism; Toll like receptor 7; Allergy; nuclear factor κB; Th1 lymphocyte; Toll like receptor; B-Vitamins; T-hox expressed in T cells; GATA-3; Transcription factor GATA3; Immunology; Immunotherapy; T-Lymphocyte; Toll-like receptors; Adjuvant; Th2 lymphocyte; Transcription factor NFκB; Immunopathology; Cytokine; Adenine; Interleukin 12; Adjuvants; Treatment; heterocycles; Homeotic gene; Interferon; TH1/TH2 lymphocytes; Allergen
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2006.05.027

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 T(H)2 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-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. 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. Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders.