Abstract
Immunotherapy for treating IgE-mediated allergies requires high doses of the corresponding allergen. This may result in undesired side effects and, to avoid them, hypoallergenic allergens (allergoids) polymerized with glutaraldehyde are commonly used. Targeting allergoids to dendritic cells to enhance cell uptake may result in a more effective immunotherapy. Allergoids coupled to yeast mannan, as source of polymannoses, would be suitable for this purpose, since mannose-binding receptors are expressed on these cells. Conventional conjugation procedures of mannan to proteins use oxidized mannan to release reactive aldehydes able to bind to free amino groups in the protein; yet, allergoids lack these latter because their previous treatment with glutaraldehyde. The aim of this study was to obtain allergoids conjugated to mannan by an alternative approach based on just glutaraldehyde treatment, taking advantage of the mannoprotein bound to the polymannose backbone. Allergoid-mannan glycoconjugates were produced in a single step by treating with glutaraldehyde a defined mixture of allergens derived from Phleum pratense grass pollen and native mannan (non-oxidized) from Saccharomyces cerevisae. Analytical and structural studies, including 2D-DOSY and 1H-13C HSQC nuclear magnetic resonance spectra, demonstrated the feasibility of such an approach. The glycoconjugates obtained were polymers of high molecular weight showing a higher stability than the native allergen or the conventional allergoid without mannan. The allergoid-mannan glycoconjugates were hypoallergenic as detected by the IgE reactivity with sera from grass allergic patients, even with lower reactivity than conventional allergoid without mannan. Thus, stable hypoallergenic allergoids conjugated to mannan suitable for using in immunotherapy can be achieved using glutaraldehyde. In contrast to mannan oxidation, the glutaraldehyde approach allows to preserve mannoses with their native geometry, which may be functionally important for its receptor-mediated recognition.
Highlights
The immunotherapy of IgE-mediated allergic diseases is based on the administration of increasing amounts of allergens to desensitize allergic patients
Coupling of allergens to mannan has been suggested as a way to enhance the allergen uptake by dendritic cells (DCs) and the efficacy of immunotherapy with allergens [10]
This approach could be even more interesting in the case of allergoids, since it has been claimed that glutaraldehyde-modified allergens are less immunogenic than native allergens due to a lower uptake by DCs [11]
Summary
The immunotherapy of IgE-mediated allergic diseases is based on the administration of increasing amounts of allergens to desensitize allergic patients (allergen vaccines). For immunotherapy to be effective, high doses of allergens have to be administered [1]. This raises major safety concerns due to the sensitivity of the patients to the allergens that the vaccine contains [1]. By means of its two reactive aldehyde groups, it cross-links the allergen proteins through the εamino groups of lysine residues. This reaction results in allergen polymerization, with the concomitant loss of accessibility of IgE antibodies to the allergen epitopes, i.e., antibody binding sites, [4]
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