Abstract
BackgroundAmong birch pollen allergic patients up to 70% develop allergic reactions to Bet v 1-homologue food allergens such as Api g 1 (celery) or Dau c 1 (carrot), termed as birch pollen-related food allergy. In most cases, specific immunotherapy with birch pollen extracts does not reduce allergic symptoms to the homologue food allergens. We therefore genetically engineered a multi-allergen chimer and tested if mucosal treatment with this construct could represent a novel approach for prevention of birch pollen-related food allergy.MethodologyBALB/c mice were poly-sensitized with a mixture of Bet v 1, Api g 1 and Dau c 1 followed by a sublingual challenge with carrot, celery and birch pollen extracts. For prevention of allergy sensitization an allergen chimer composed of immunodominant T cell epitopes of Api g 1 and Dau c 1 linked to the whole Bet v 1 allergen, was intranasally applied prior to sensitization.ResultsIntranasal pretreatment with the allergen chimer led to significantly decreased antigen-specific IgE-dependent β-hexosaminidase release, but enhanced allergen-specific IgG2a and IgA antibodies. Accordingly, IL-4 levels in spleen cell cultures and IL-5 levels in restimulated spleen and cervical lymph node cell cultures were markedly reduced, while IFN-γ levels were increased. Immunomodulation was associated with increased IL-10, TGF-β and Foxp3 mRNA levels in NALT and Foxp3 in oral mucosal tissues. Treatment with anti-TGF-β, anti-IL10R or anti-CD25 antibodies abrogated the suppression of allergic responses induced by the chimer.ConclusionOur results indicate that mucosal application of the allergen chimer led to decreased Th2 immune responses against Bet v 1 and its homologue food allergens Api g 1 and Dau c 1 by regulatory and Th1-biased immune responses. These data suggest that mucosal treatment with a multi-allergen vaccine could be a promising treatment strategy to prevent birch pollen-related food allergy.
Highlights
One of the most common type I pollionosis is caused by the airborne allergens of birch pollen (BP)
These data suggest that mucosal treatment with a multi-allergen vaccine could be a promising treatment strategy to prevent birch pollen-related food allergy
Based on previous T cell epitope mapping experiments with Api g 1 and Dau c 1 the immunodominant regions of these allergens were selected for designing the Bet v 1-food allergen chimer
Summary
Intranasal Pretreatment with Bet v 1, Api g 1 and Dau c 1 Alone or as a Mixture does not Suppress Immune Responses Against All 3 Allergens. In poly-sensitized mice, mucosal pretreatment with a mixture of all 3 allergens significantly reduced basophil degranulation to Bet v 1, but not to the homologous food allergens (Fig. 2B). Intranasal pretreatment with the chimer significantly reduced IgE-mediated basophil degranulation to all three allergens in comparison to the untreated poly-sensitized group (Fig. 4A). Pretreatment with the chimer increased serum levels of total and allergen-specific IgA antibodies in comparison to poly-sensitized controls (Fig. 4C). IFN-c production in spleen cell cultures was significantly enhanced after Bet v 1 - but not after Api g 1 or Dau c 1 stimulations compared to poly-sensitized controls (Fig. 5B). Application of anti-TGF-b, anti-IL10R or anti-CD25 blocking antibodies significantly abrogated the suppression of IL-5 and IL-4 production in spleen cell cultures of chimer-treated mice (Fig. 7A). The percent suppression mediated by Treg cells isolated from chimer-treated mice was 4.8-fold higher (ratio 1/2) than Tregs derived from poly-sensitized mice
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