Recognition of allergen epitopes in secondary IgE responses

IgE-mediated allergies represent a global health problem with a continuously increasing prevalence. The hallmark of allergic disease is the production of IgE-antibodies against environmental allergens. Subsequent allergen contact leads to a boost of allergen-specific IgE responses and thus to the progression of the disease. Although IgE plays a central role in the pathogenesis of allergic disease the mechanisms underlying allergen-specific IgE antibody production in allergic patients are not fully understood. This project will investigate the regulation of secondary allergen-specific IgE responses in a murine model with the aim to answer the following questions: 1. Establishment of a mouse model for boosting allergen-specific IgE antibody responses In this part of the project we will establish a mouse model, which allows the sensitization to the major pollen- derived allergens Bet v 1 and Phl p 1 without priming allergen-specific T cells. Using this model we will address the question whether the secondary IgE response to allergens is T cell dependent. Currently different approaches for vaccination / tolerance induction targeting different cell types are under development (e.g. T cell epitope-based vaccines, vaccines based on recombinant allergens or allergen derivatives). The identification of the cells involved in the regulation of secondary allergen-specific IgE antibody responses should therefore be of great importance for the development of new treatment strategies. Results obtained from these experiments may help to define the target cells which should be addressed by an intervention. 2. Immunoregulatory role of antibodies The second part of the project will investigate the question whether other antibody classes beside IgE play a role in regulating allergen-specific IgE responses (Suppression / Enhancement?) and if IgG antibodies interfering with the recognition of allergens by IgE antibodies are able to prevent the boost of allergen-specific IgE. Answering these questions may contribute to the development of therapeutic strategies based on immunoregulatory or protective antibodies (e.g. passive immunization by administration of allergen-specific IgG antibodies). 3. The cellular origin of secondary IgE responses The last part of the project addresses the questions what cells are responsible for the secondary IgE response are where they are located and how this secondary IgE response can be boosted. The identification and localisation of these cells may give rise to new treatment targeted strategies aiming to deplete cells responsible for IgE production.

Type 1 allergy is an antibody-mediated disease affecting about 25% of the population. Allergic patients produce antibodies of the IgE class against harmless environmental antigens (allergens), which elicit allergic symptoms after allergen contact. Little is known about how the production of allergen-specific IgE is maintained over long time periods and which factors lead to an increase of secondary IgE production in patients. In this project the particular question whether an increased IgE production after allergen contact is dependent on T cell help was investigated. We developed a mouse model in which allergic mice received different allergen components that could be recognized only by B or T lymphocytes. It was shown that a boost of allergen-specific IgE production could occur without T cell help. These results were strongly supported by a study in atopic dermatitis patients, who received long term treatment with cyclosporine A. While the T cell-mediated skin symptoms were reduced in these patients, the rise of allergen-specific IgE during the pollen season was unaffected. These results are important for a better understanding of ellergic disease but also for the development of therapeutic strategies.