IN VIVO REGULATION OF IGE PRODUCTION

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DESCRIPTION: (Adapted from the Investigator's abstract): Exacerbated immune responses to environmental airborne non-pathogenic antigens (allergens) are one of the main factors for the development of asthma. Allergic reactions in the airways are triggered by antigen crosslinking of IgE molecules on mast cells, leading to degranulation and release of active mediators of smooth muscle constriction and inflammation. It has been shown that one of the essential determinant of allergic responses is the stimulation of T helper lymphocytes of the type 2 (Th2), which, through cognate T/B interaction and IL-4 secretion mediate B lymphocyte switch to IgE production, and through the secretion of IL-5, regulate the recruitment, differentiation and activation of eosinophils. This application is focused on the in vivo regulation of IgE production. Using homologous recombination, we have inserted a rearranged VDJ heavy chain gene as well as a rearranged VJ light chain gene from an influenza hemagglutinin-specific B cell hybridoma into the genome of mice. B cells from these mice maintain the physiological elements controlling somatic hypermutation and isotype switching, but, contrary to normal mice, the fate of antigen-specific cells can be easily followed. These mice will enable us to assess the relative importance of the different signals which promote isotype switching to IgE, thus defining ways in which the generation of IgE could be prevented or downregulated. Specifically, we will: 1) determine the conditions which favor the generation of antigen-specific IgE in vivo; 2) assess the importance of the affinity of the B cell receptor for its antigen on immunoglobulin class switch; 3) determine whether non-IgE antibodies expressing the same antigen-specificity of IgE antibodies can modulate the response in the airways, and 4) determine whether T cells are involved in the downregulation of IgE responses. We believe that the proposed experiments will enhance our knowledge on the regulation of IgE production in response to antigen, and will open new avenues for therapy of atopic disease.