Use of a genetic cholera toxin B subunit/allergen fusion molecule as mucosal delivery system with immunosuppressive activity against Th2 immune responses

ArticleinVaccine 25(50):8395-404 · January 2008with15 Reads
DOI: 10.1016/j.vaccine.2007.10.003 · Source: PubMed
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 [111]. 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 [112]. 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 [113]. "
    [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.
    Full-text · Article · Apr 2013
    • "Effector T cell apoptosis was found to be critically dependent on CD25 + Treg cells but independent of IL-10 production. In contrast, Bublin et al. [49], using the Betv1a-CTB conjugate by the intranasal route in a model of allergic sensitization, showed that upregulation of Foxp3, IL-10 and TGFβ mRNA expression was detected in splenocytes but only after pretreatment with unconjugated allergen and not with the fusion molecule, indicating that antigen conjugation to a mucosal carrier modifies the immunomodulating properties of an antigen/allergen. Of note, opposite effects on IgE production, lymphocyte proliferation and cytokine production had already been reported by Wiedermann et al. [50] after intranasal administration of OVA-CTB and rBetv1a-CTB. "
    [Show abstract] [Hide abstract] ABSTRACT: Cholera toxin (CT) and the heat-labile enterotoxin of E. coli (LT), as well as their non toxic mutants, are potent mucosal adjuvants of immunization eliciting mucosal and systemic responses against unrelated co-administered antigens in experimental models and in humans (non toxic mutants). These enterotoxins are composed of two subunits, the A subunit, responsible for an ADP-ribosyl transferase activity and the B subunit, responsible for cell binding. Paradoxically, whereas the whole toxins have adjuvant properties, the B subunits of CT (CTB) and of LT (LTB) have been shown to induce antigen specific tolerance when administered mucosally with antigens in experimental models as well as, recently, in humans, making them an attractive strategy to prevent or treat autoimmune or allergic disorders. Immunomodulation is a complex process involving many cell types notably antigen presenting cells and regulatory T cells (Tregs). In this review, we focus on Treg cells and cholera-like enterotoxins and their non toxic derivates, with regard to subtype, in vivo/in vitro effects and possible role in the modulation of immune responses to coadministered antigens.
    Full-text · Article · Jul 2010
    • "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). "
    Article · · Toxins
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