Determination of Cellular and Clinical Thresholds for IgE-Mediated Reactivity

Johns Hopkins University, Baltimore MD

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Abstract

While the detection of allergen-specific IgE, either by skin testing or in vitro assays, is a useful marker of[unreadable] allergic sensitivity, the relationship between specific IgE levels and allergic responses is far from clear. In[unreadable] fact, for food, drug, insect sting and inhalant allergens most studies have shown no relationship between[unreadable] the levels of specific IgE and type or severity of responses to allergen exposure. The lack of such a[unreadable] relationship may be due to a variety of factors that we propose to investigate in the clinical and ex vivo[unreadable] studies described in this project. A central hypothesis to be tested is that a combination of the allergen-specific[unreadable] IgE and total IgE levels, especially the ratio of these two measurements, by influencing FceRI[unreadable] occupancy and density, determines the threshold and likelihood for cellular and clinical reactivity. This[unreadable] hypothesis is based in part on what our group and other laboratories have learned about how IgE, and an[unreadable] FDA-approved IgE-lowering antibody therapy, omalizumab, regulates basophil and mast cell[unreadable] responsiveness and surface density of FceRI. Given the half-life of mast cells in different tissue[unreadable] compartments and the slower onset of action of omalizumab on mast cells compared to that for basophils,[unreadable] we propose to test the hypothesis that food-induced anaphylaxis and late phase responses are basophildependent[unreadable] responses by performing skin, airway and oral allergen challenge within the first two weeks,[unreadable] and after months, of omalizumab administration. We also hypothesize that mechanisms responsible for[unreadable] trafficking of eosinophils to sites of airway late phase responses involve IgE-mediated triggering of[unreadable] recruited basophils, which then release mediators capable of activating epithelial chemokine production[unreadable] selective for eosinophils. As part of these efforts, we propose to develop a new and reliable diagnostic test[unreadable] for the measurement of free total serum IgE levels in collaboration with colleagues in Core B. Our overall[unreadable] goal is to expand our knowledge of the biology of IgE and its clinical relevance using an approved anti-lgE[unreadable] antibody, omalizumab, as a mechanistic tool to modulate free IgE levels.