Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1
Sofía Sirvent, Irene Soria, Cristina Cirauqui, Bárbara Cases, Ana I Manzano, Carmen M Diez-Rivero, Pedro A Reche, Juan López-Relaño, Eduardo Martínez-Naves, F Javier Cañada, Jesús Jiménez-Barbero, Javier Subiza, Miguel Casanovas, Enrique Fernández-Caldas, José Luis Subiza, Oscar Palomares, Sofía Sirvent, Irene Soria, Cristina Cirauqui, Bárbara Cases, Ana I Manzano, Carmen M Diez-Rivero, Pedro A Reche, Juan López-Relaño, Eduardo Martínez-Naves, F Javier Cañada, Jesús Jiménez-Barbero, Javier Subiza, Miguel Casanovas, Enrique Fernández-Caldas, José Luis Subiza, Oscar Palomares
Abstract
Background: Allergen immunotherapy (AIT) is the only curative treatment for allergy. AIT faces pitfalls related to efficacy, security, duration, and patient compliance. Novel vaccines overcoming such inconveniences are in demand.
Objectives: We sought to study the immunologic mechanisms of action for novel vaccines targeting dendritic cells (DCs) generated by coupling glutaraldehyde-polymerized grass pollen allergoids to nonoxidized mannan (PM) compared with glutaraldehyde-polymerized allergoids (P) or native grass pollen extracts (N).
Methods: Skin prick tests and basophil activation tests with N, P, or PM were performed in patients with grass pollen allergy. IgE-blocking experiments, flow cytometry, confocal microscopy, cocultures, suppression assays, real-time quantitative PCR, ELISAs, and ELISpot assays were performed to assess allergen capture by human DCs and T-cell responses. BALB/c mice were immunized with PM, N, or P. Antibody levels, cytokine production by splenocytes, and splenic forkhead box P3 (FOXP3)(+) regulatory T (Treg) cells were quantified. Experiments with oxidized PM were also performed.
Results: PM displays in vivo hypoallergenicity, induces potent blocking antibodies, and is captured by human DCs much more efficiently than N or P by mechanisms depending on mannose receptor- and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-mediated internalization. PM endorses human DCs to generate functional FOXP3(+) Treg cells through programmed death ligand 1. Immunization of mice with PM induces a shift to nonallergic responses and increases the frequency of splenic FOXP3(+) Treg cells. Mild oxidation impairs these effects in human subjects and mice, demonstrating the essential role of preserving the carbohydrate structure of mannan.
Conclusions: Allergoids conjugated to nonoxidized mannan represent suitable vaccines for AIT. Our findings might also be of the utmost relevance to development of therapeutic interventions in other immune tolerance-related diseases.
Keywords: Allergen immunotherapy; allergoids; dendritic cells; immunomodulation; mannan; neoglycans; regulatory T cells; vaccines.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed