A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

详细信息    查看全文

• 作者：Lucia Fil¨¬ ; Aless ; ra Vultaggio ; Elisa Cardilicchia ; Cinzia Manuelli ; Andrea Casini ; Francesca Nencini ; Laura Maggi ; Sara Pratesi ; Giulia Petroni ; Francesca Boscaro ; Antonio Guarna ; Ernesto G. Occhiato ; Sergio Romagnani ; Enrico Maggi ; Paola Parronchi
• 关键词：Adjuvants ; immunotherapy ; allergy ; vaccines ; Toll-like receptors ; adenine derivatives ; TH cells
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：132
• 期：1
• 页码：84-92.e6
• 全文大小：766 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

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-¦Á 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_H2-related cytokines and increased IFN-¦Ã 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-¦Ã upregulation together with IgE downregulation, and an increase in allergen-specific IgG_2a levels in sera. The conjugate exhibited reduced ability to activate human Fc¦ÅRI⁺ cells without inducing T_H17 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_H2 responses without eliciting harmful effects.