Cholera toxin B subunit as a carrier for inducing mucosal immunity and/or peripheral tolerance

Abstract

When an antigen is introduced via a mucosal route, either immunity or tolerance, or even both may be induced. Both immunity and tolerance are actively induced phenomena and both of them could have important medical implications as well as potential prophylactic or therapeutic applications. Induction of local immunity in the mucosa is an important objective of vaccines that should protect against pathogens entering via a mucosal route. By inducing tolerance, deleterious immune responses against normally harmless antigens such as autoantigens and allergens could be prevented. In this thesis, it is studied in mice whether mucosal administration of antigens physically coupled to a specific carrier protein with mucosa binding properties, Cholera toxin B subunit - a component of a registered oral cholera vaccine, would induce or modulate either or both of these phenomena.Induction of mucosal immunityThe most efficient route for stimulating local immunity in the genital tract was determined. It was shown that the vaginal route, and somewhat unexpectedly also the intranasal route were efficient for inducing antibody responses in the genital tract. These responses could be enhanced by conjugation of the antigen to CTB, prior to mucosal administration. The carrier efficacy of CTB was compared with that of the closely related protein, E. coli heat labile enterotoxin (LTB), which also has mucosa binding properties. CTB was superior to LTB as a carrier by the peroral route, but not by the intranasal or vaginal routes of immunization. It was also investigated whether CTB had adjuvant properties for simply admixed, not coupled antigens. Indeed, by the vaginal and intranasal routes of immunization, but not the peroral route of immunization, CTB was shown to increase the antibody response to the co-administered antigen.Induction of peripheral toleranceThe ability of CTB to act as a carrier for inducing tolerance to IgE mediated type I hypersensitivity reactions was studied. It was shown that peroral or intranasal administration of CTB coupled to a common dietary allergen ovalbumin (OVA), efficiently prevented the induction of IgE antibody responses in OVA allergy-sensitized animals. Even more important from a potential clinical application point of view, mucosal administration of coupled material could interfere with an already established IgE antibody response. In contrast, mucosal administration of CTB coupled to a birch pollen allergen, instead of inducing tolerance, stimulated the IgE antibody response.It is concluded that CTB is a good carrier for inducing both mucosal antibody responses and peripheral tolerance. However, as illustrated for the IgE antibody response to two allergens, there are differences depending on the nature of the antigen. Further studies need to evaluate whether the promising results in animals, of using CTB-antigen conjugates for either stimulating or suppressing the immune response, will hold true also for humans.