High-dose allergen exposure leads to tolerance

Reports of decreased sensitization to cat allergen (Fel d 1) among individuals living with a cat or subjects exposed to high-dose cat allergen may be explained by the development of a form of high-dose tolerance resulting from natural exposure to an inhalant allergen. Although the epidemiological data regarding the relationship between exposure and sensitization to Fel d 1 are conflicting, the ability for high-dose Fel d 1 to induce a characteristic nonallergic immune response with a distinctive serum antibody profile has been established. Definition of this modified T-helper (Th)2 response to cat allergen, coupled with the renewed interest in regulatory T cells within the immunology field, has provided an avenue for exploring the mechanism by which IgE antibody-mediated responses are controlled. There is mounting evidence to suggest that the modified Th2 response is a variation of the allergic response and that the modified Th2-allergic axis is influenced by allergen dose and genetics. This article discusses putative immune mechanisms of tolerance within the context of an allergen-specific system. The relevance of high-dose allergen exposure and alternate factors such as endotoxin to the development of tolerance is considered. Fel d 1 exhibits unique molecular and immunological characteristics that may contribute to its tolerogenic properties. Major T-cell epitopes of Fel d 1 that preferentially induce regulatory factors have been defined. Furthermore, hightiter IgE antibody responses associated with atopic dermatitis are characterized by a defect in the T-cell repertoire that is specific to these epitopes. Identification of Fel d 1 epitopes that induce interleukin-10 may provide new targets for treatment.