Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 132, Issue 1, Pages 84-U168Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2013.01.030
Keywords
Adjuvants; immunotherapy; allergy; vaccines; Toll-like receptors; adenine derivatives; T-H cells
Categories
Funding
- Regione Toscana (Regional Health Research Program)
- Ente Cassa di Risparmio di Firenze
- FP6 European Union project SENS.IT.IV [LSHB-CT-2006-018861]
- FP6 European Union project INNOCHEM [FP6-LSHB-CT-2005-518167]
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Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of T-H-related transcription factors. Lung cells and sera of nDer p 2-Conj-sensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2-Conj stimulated IL-12 and IFN-alpha production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T(H)2-related cytokines and increased IFN-gamma levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-gamma upregulation together with IgE downregulation, and an increase in allergen-specific IgG(2a) levels in sera. The conjugate exhibited reduced ability to activate human FceRI(+) cells without inducing T(H)17 cells or autoantibodies. Conclusions: The codelivery of an allergen with a modified adenine as a conjugate inducing modulatory cytokines from innate cells redirects in vitro and in vivo pathogenic T(H)2 responses without eliciting harmful effects.
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