Bublin, M., Hoflehner, E., Wagner, B., Radauer, C., Wagner, S. & Hufnagl, K. et al. Use of a genetic cholera toxin B subunit/allergen fusion molecule as mucosal delivery system with immunosuppressive activity against Th2 immune responses. Vaccine 25,, 8395-8404
Induction of peripheral tolerance can be facilitated when the antigen is linked to the B subunit of cholera toxin (CTB), an efficient mucosal carrier. In the present study, a genetic fusion molecule of Bet v 1 and CTB was produced to test whether mucosal application of this construct would lead to suppression of Th2 responses. Intranasal pretreatment of BALB/c mice with rCTB-Bet v 1 prior to allergic sensitisation with the allergen significantly decreased IgE but markedly increased allergen-specific IgG2a levels in sera as well as IFN-gamma production of splenocytes. This Th1 shift was supported by an increased T-bet/GATA3 mRNA ratio. IL-5 production within the airways was suppressed after the pretreatment with rCTB-Bet v 1, while local allergen-specific IgA antibodies were markedly enhanced by pretreatment with the construct. Upregulation of Foxp3, IL-10 and TGF-beta mRNA expression was detected in splenocytes after pretreatment with unconjugated allergen but not with the fusion molecule, indicating that antigen conjugation to a mucosal carrier modifies the immunomodulating properties of an antigen/allergen.
"In a delayed type hypersensitivity model, (prolonged) oral treatment with low doses of OVA conjugated to CTB prevented sensitization and suppressed IgE antibody responses in sensitized mice . Furthermore, intranasal pretreatment of CTB linked to the BetV1, a major allergen of birch pollen, prevented sensitization to the antigen by shifting the Th2 response towards Th1 and the induction of allergen-specific IgA responses . Likewise, we found that CTB administration in the lungs stimulates local secretory IgA responses which protected against the development of allergic airway inflammation (AAI), while mice deficient for polymeric Ig receptor (pIgR) and lacking SIgA were not . "
[Show abstract][Hide abstract] ABSTRACT: Allergic asthma is characterized by bronchial hyperresponsiveness, a defective barrier function, and eosinophilic lower airway inflammation in response to allergens. The inflammation is dominated by Th2 cells and IgE molecules and supplemented with Th17 cells in severe asthma. In contrast, in healthy individuals, allergen-specific IgA and IgG4 molecules are found but no IgE, and their T cells fail to proliferate in response to allergens, probably because of the development of regulatory processes that actively suppress responses to allergens. The presence of allergen-specific secretory IgA has drawn little attention so far, although a few epidemiological studies point at a reverse association between IgA levels and the incidence of allergic airway disease. This review highlights the latest literature on the role of mucosal IgA in protection against allergic airway disease, the mechanisms described to induce secretory IgA, and the role of (mucosal) dendritic cells in this process. Finally, we discuss how this information can be used to translate into the development of new therapies for allergic diseases based on, or supplemented with, IgA boosting strategies.
"Administration av allergenet, menar Bublin et al. (2007), kan även ske via de nasala slemhinnorna eller oralt, då vanligen under tungan. Vidare menar Bublin et al. (2007) dock att det krävs högre doser av allergen vid denna typ av administration jämfört med intravenös dosering. Alternativa doseringsmetoder varierar doseringsintervallerna i starten av behandlingen tills rätt koncentration uppnåtts, exempelvis klusterdoseringar med flera injektioner upprepade veckovis (Massanari et al. 2010), eller påskyndade doseringar där hela upptrappningen till rätt koncentration som kortast kan avklaras på en dag (Frew 2010). "
"However, we have shown that the immunosuppressive properties of CTB are influenced by the nature of the coupled antigen as well as by the mode of conjugation: ovalbumin chemically coupled to CTB led to reduction, while Bet v 1 chemically coupled to CTB enhanced allergic immune responses (Wiedermann et al., 1999b). In order to improve the immunomodulatory property of CTB we recently genetically engineered a Bet v 1-CTB fusion molecule (Bublin et al., 2007). The clear advantage of a recombinant fusion molecule over a chemical conjugate is its homogeneity, since the molecular composition and position of the antigen do not vary and the amount of antigen is increased to five molecules per one molecule CTB pentamer. "
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that a reduced or changed pattern of exposure to certain microorganisms has led to an unbalanced regulation of our im-mune system with consequently increased development of inflamma-tory diseases, such as allergic or autoimmune disorders. Studies on the basis of this so called "hygiene hypothesis" have concentrated on identifying microorganisms that may have the potential to re-establish a regulatory network important to prevent or counteract immune overreactions to innocuous antigens leading to immunopathology. Using mouse models of type I allergy/asthma we tested several ap-proaches to prevent or treat allergic immune responses, either by the use of mucosal adjuvants, the application of certain lactic acid bacteria as antigen delivery systems or by parasite inoculation. The goal of our research is to exploit the underlying mechanisms of immune modula-tion and to identify some of the microbial components with immuno-modulatory properties, which may serve as novel treatment tools against inflammatory disorders, including allergic diseases.
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