Regulatory role of allergen-specific antibodies

Type I allergy represents a global health problem affecting more than 25% of the population worldwide. The recognition of allergens by specific IgE antibodies is a key event for the initiation of allergic inflammation. A major hurdle for the characterization of allergen-specific IgE antibodies from allergic patients is that they occur in extremely low amounts in serum and other body fluids. Within this project the applicant will obtain cDNAs coding for allergen-specific human IgE antibodies by RT-PCR from the peripheral blood of allergic patients with a defined allergen profile at different time points (i.e., before and after allergen exposure) to analyze the human IgE VH repertoire for defined allergens. This will allow answering questions regarding the diversity and plasticity of the allergen-specific IgE repertoire. The isolated IgE heavy chain variable regions will then be re-combined with the light chain repertoire to study the rules of pairing of heavy and light chains for obtaining allergen-specificity. IgE- derived allergen-specific antibody fragments will be converted into complete human IgE antibodies to determine the impact of affinity, clonality, and epitope recognition on the effector cell degranulation in response to allergens. The results from these studies should provide information regarding the factors underlying the "allergenic activity" of allergens. Results from the in vitro studies will be translated into an in vivo model by populating transgenic mice expressing the human Fc?RI with allergen-specific IgE antibodies. Within this models it is planned to investigate airway hyperresponsiveness as a surrogate for allergic asthma by challenging these mice with defined allergen molecules. In parallel, the applicant will convert allergen-specific human IgE antibodies into allergen-specific human IgG antibodies and investigate their therapeutic potential in the mouse model.

Type I allergy represents a global health problem affecting more than 25% of the population worldwide. The recognition of allergens by specific IgE antibodies is a key event for the initiation of allergic inflammation. A major drawback for the characterization of allergen-specific IgE antibodies from allergic patients and hence the understanding of the underlying mechanisms of Type I allergy is that IgE antibodies occur in extremely low amounts in serum and other body fluids. Within the scope of this project we succeeded in identifying significant properties of human allergen-specific IgE antibodies that directly contribute in the aggravation of the disease. Our newly acquired knowledge could be used for the development of more effective hypoallergenic derivatives to improve efficacy and safety of the specific immunotherapy.Furthermore, we found a clear explanation why not every SIT-induced IgG antibody cross-protects against cross-reactive allergens. This finding is an additional reason to work on the improvement of the currently practised SIT.We could also show for the first time in a mouse model that passive immunization with protective pollen allergen-specific IgG antibodies is effective for treatment and prevention of allergy.