Mechanistic Analysis of Anti-IgE Therapy of Asthma

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Morbidity and mortality from asthma have been found to be disproportionately high in the inner-city pediatric population compared to other pediatric populations. Over the last several years, the Inner City Asthma Study (ICAS) group has focused on a variety of potential factors that may account for this health disparity. Studies to date indicate that the majority of inner-city children with asthma are sensitized to a number of indoor environmental allergens. However, while IgE-mediated immune responses are known to play an important role in allergic diseases, including allergic asthma, the clinical relevance of this high degree of allergen sensitivity in this inner-city population currently is not clearly known. In order to better understand the role played by IgE antibodies in allergic asthma, a therapeutic trial using RhuMab-E25, a humanized murine monoclonal anti-lgE antibody, will be carried out in inner-city asthmatic children by 6 of the 7 ICAS sites. The proposed mechanistic studies will seek to elucidate the immunomodulatory mechanisms underlying the clinical effects of RhuMab-E25 therapy. This agent has been shown to modulate both basophil and mast cell function and to suppress the late-phase asthmatic response and possibly B cell IgE synthesis in humans. In addition, monoclonal anti-lgE treatment of mice leads to altered Th2 cytokine profiles. These findings indicate that IgE plays a major role in orchestrating the complex inflammatory events that occur in asthma and that RhuMab-E25 may act on multiple effector cells. In the mechanistic studies, we will address three specific aims. Specifically, we will: a) determine if children who have the highest dust mite-and/or cockroach-specific IgE levels will demonstrate the most clinical benefit from RhuMab- E25 therapy; b) determine if RhuMab-E25 therapy will lead to decreased allergen-driven Th2 cytokine production and increased Th1 cytokine production by patient peripheral blood mononuclear cells; and c) determine if polymorphisms in genes associated with IgE synthesis and/or function are responsible for individual variation in response to RhuMab-E25 therapy. These studies will allow us to better understand the cellular and molecular events associated with RhuMab-E25 therapy and they will allow us to determine which allergic diseases as well as which patient populations will receive the most therapeutic benefit. >