Cholera toxin B suppresses allergic inflammation through induction of secretory IgA

Abstract

In healthy individuals, humoral immune responses to allergens consist of serum IgA and IgG4, whereas cellular immune responses are controlled by regulatory T (Treg) cells. In search of new compounds that might prevent the onset of allergies by stimulating this type of immune response, we have focused on the mucosal adjuvant, cholera toxin B (CTB), as it induces the formation of Treg cells and production of IgA. Here, we have found that CTB suppresses the potential of dendritic cells to prime for Th2 responses to inhaled allergen. When we administered CTB to the airways of naïve and allergic mice, it strongly suppressed the salient features of asthma, such as airway eosinophilia, Th2 cytokine synthesis, and bronchial hyperreactivity. This beneficial effect was only transferable to other mice by transfer of B but not of T lymphocytes. CTB caused a transforming growth factor-beta-dependent rise in antigen-specific IgA in the airway luminal secretions, which was necessary for its preventive and curative effect, as all effects of CTB were abrogated in mice lacking the luminal IgA transporting polymeric Ig receptor. Not only do these findings show a novel therapeutic avenue for allergy, they also help to explain the complex relationship between IgA levels and risk of developing allergy in humans.

Interaction of Cholera Toxin B Subunit with Intestinal Epithelial Cells

“…Recombinant CT-B has been recently found to suppress immunopathological reactions in allergy and autoimmune diseases to stimulate humoral immunity and to induce anti inflammatory responses in vivo, in particular, to mitigate the intestinal inflammation of Crohn's disease in mice and humans [25,29,2,28]. Since CT-B can prevent infection but also autoimmune reactions, the question is how these two apparently opposite immune reactions can be achieved by the same protein.…”

Strategies of mucosal immunotherapy for allergic diseases

“…51 Smits et al found that intratracheal administration of CTB can suppress allergic inflammation through the induction of airway luminal IgA secretions in a TGF-b-dependent manner, which is necessary for its preventive and curative effect. 52 CpG oligodeoxynucleotides (CpG ODNs). CpG ODNs contain unmethylated CpG motifs, which confer the immunostimulatory properties of bacterial DNA through the ability to induce immune responses.…”

“…Additionally, a doubleblind, placebo-controlled study was conducted to examine the 47 Monomeric allergoid (Lais, Lofarma S.p.A., Milan) for mite-sensitized patients with rhinitis and intermittent asthma/SLIT 48,49 Adjuvants for mucosal immunotherapy Cholera toxin B/i.t. 52 No recent study for allergic diseases CpG ODNs/i.t. 53 and i.n.…”

A plant-made cholera toxin B subunit enhances mucosal wound healing and protects against ulcerative colitis and colon cancer.

“…In a rat model of kidney transplantation, an anti-inflammatory D-amino acid decapeptide, RDP58, chemically conjugated to CTB was shown to enhance the survival time compared to the therapeutic compound alone (71). Allergic inflammation in mouse airways has also been shown to be reduced by CTB administration, not only in a preventative sense but also in mice that have already been sensitized to airway inflammation (60 A) Commercial non-recombinant CTB containing a trace amount of CT (CTB+CT) significantly reduces the production of TNF-α due to LPS stimulation. Raw 264.7 cells were pretreated with 10 μg/ml rCTB (produced in E. coli (76)), CTB+CT (Sigma-Aldrich, catalog no.…”

“…Indeed, the protein was shown to suppress immunopathological reactions in allergy and autoimmune diseases (reviewed in: (59)). In a mouse model, the airway administration of CTB ameliorated experimental asthma (60).…”