title: 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 (40kDa) and low (6kDa) 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.
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Weinberger
authors.forename: Martin
authors.initials: M
authors.lastname: Himly
authors.forename: Julia
authors.initials: J
authors.lastname: Myschik
authors.forename: Michael
authors.initials: M
authors.lastname: Hauser
authors.forename: Friedrich
authors.initials: F
authors.lastname: Altmann
authors.forename: Almedina
authors.initials: A
authors.lastname: Isakovic
authors.forename: Sandra
authors.initials: S
authors.lastname: Scheiblhofer
authors.forename: Josef
authors.initials: J
authors.lastname: Thalhamer
authors.forename: Richard
authors.initials: R
authors.lastname: Weiss
mesh_terms: D000485:Allergens / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D000818:Animals; D029441:Carica / Q000737:chemistry; D002460:Cell Line; D002645:Chickens; D003713:Dendritic Cells / Q000276:immunology; D003888:Desensitization, Immunologic / Q000379:methods*; D016503:Drug Delivery Systems; D005260:Female; D006001:Glycoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D010206:Papain / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D010940:Plant Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D051381:Rats
chemical_list: D000485:Allergens; D006001:Glycoconjugates; D007074:Immunoglobulin G; D010940:Plant Proteins; D010047:Ovalbumin; D010206:Papain