Generation of hypoallergenic neoglycoconjugates for dendritic cell targeted vaccination: A novel tool for specific immunotherapy

Abstract

The incidence of allergic disorders and asthma continuously increased over the past decades, consuming a considerable proportion of the health care budget. Allergen-specific subcutaneous immunotherapy represents the only intervention treating the underlying causes of type I allergies, but still suffers from unwanted side effects and low compliance. There is an urgent need for novel approaches improving safety and efficacy of this therapy. In the present study we investigated carbohydrate-mediated targeting of allergens to dermal antigen-presenting cells and its influence on immunogenicity and allergenicity. Mannan, high (40 kDa) and low (6 kDa) molecular weight dextran, and maltodextrin were covalently attached to ovalbumin and papain via mild carbohydrate oxidation resulting in neoglycocomplexes of various sizes. In particular, mannan-conjugates were efficiently taken up by dendritic cells in vivo leading to elevated humoral immune responses against the protein moiety and a shift from IgE to IgG. Beyond providing an adjuvant effect, papain glycocomplexes also proved to mask B-cell epitopes, thus rendering the allergen derivative hypoallergenic.The present data demonstrate that carbohydrate-modified allergens combine targeting of antigen presenting cells with hypoallergenicity, offering the potential for low dose allergen-specific immunotherapy while concomitantly reducing the risk of side effects.

Vaccination and Other Antigen-Specific Immunomodulatory Strategies in Celiac Disease

“…Therefore, we speculated that the transamidation of dominant peptides might favor HLA binding of low-affinity, subdominant or cryptic, gliadin determinants with dramatic consequences for the immune outcome. This hypothesis appears to be in line with another study showing that masking B-cell epitopes by coupling carbohydrates to the protein surface made the protein hypoallergenic but still able to elicit elevated IgG titers following intradermal immunization [47]. Importantly, if primed by immunization, T cell populations specific for subdominant/cryptic epitopes were not diluted out by the preferential outgrowth of T cells directed to the dominant epitopes [48].…”

Potential of nanoparticles for allergen-specific immunotherapy – use of silica nanoparticles as vaccination platform

“…Another approach to reduce allergenicity of proteins and develop hypoallergenic molecules is to utilize carbohydrates in order to mask IgE epitopes 58,59 . Moreover, carbohydrates can be applied for both, specific targeting of antigen presenting cells as well as modulating the resulting immune response [60][61][62] .…”

“…Intradermal immunization of these neoglycoconjugates showed that antigen presenting cells of the skin can be addressed via carbohydrate-specific receptors and thereby increase the immunogenicity of the vaccine. Moreover, this approach does not induce novel IgE production, but instead triggers strong production of IgG, which can act as so-called blocking antibodies 3,59 .…”

“…We have recently demonstrated that nanoparticles generated by crosslinking of allergens with carbohydrates fulfill the most important requirements for safe and efficient immunotherapy 59 . For example mannan, a biodegradable linear polymer of 1,4-linked mannose residues is a promising candidate for drug nanocarrier systems 110 .…”

Nanoparticle Based-immunotherapy Against Allergy

“…An extra limitation of the classical subcutaneous immunotherapy is the phobia in some patients to the needles and the risk associated with the use of needles [12]. Consequently, attempts for safer and more convenient and efficacious strategies are in search: generation of recombinant allergens which give no IgE-mediated activation, hypoallergenic glycoconjugates, new adjuvants favoring specific Th1 responses, and, moreover, different routes of application specific immunotherapy (SIT) especially sublingual, epicutaneous, and intra-lymphatic delivery of the allergen [13][14][15]. In the current review we will focus on nanoparticles (NP) as adjuvants for allergy immunotherapy.…”