Morbidity and mortality from asthma have been found to be disproportionately high in the inner-city pediatricpopulation 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 todate indicate that the majority of inner-city children with asthma are sensitized to a number of indoor environmentalallergens. However, while IgE-mediated immune responses are known to play an important role in allergicdiseases, including allergic asthma, the clinical relevance of this high degree of allergen sensitivity in this inner-citypopulation currently is not clearly known. In order to better understand the role played by IgE antibodies in allergicasthma, a therapeutic trial using RhuMab-E25, a humanized murine monoclonal anti-lgE antibody, will be carriedout in inner-city asthmatic children by 6 of the 7 ICAS sites. The proposed mechanistic studies will seek toelucidate the immunomodulatory mechanisms underlying the clinical effects of RhuMab-E25 therapy. This agenthas been shown to modulate both basophil and mast cell function and to suppress the late-phase asthmaticresponse and possibly B cell IgE synthesis in humans. In addition, monoclonal anti-lgE treatment of mice leads toaltered Th2 cytokine profiles. These findings indicate that IgE plays a major role in orchestrating the complexinflammatory events that occur in asthma and that RhuMab-E25 may act on multiple effector cells. In themechanistic studies, we will address three specific aims. Specifically, we will: a) determine if children who havethe 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 productionand increased Th1 cytokine production by patient peripheral blood mononuclear cells; and c) determine ifpolymorphisms in genes associated with IgE synthesis and/or function are responsible for individual variation inresponse to RhuMab-E25 therapy. These studies will allow us to better understand the cellular and molecularevents associated with RhuMab-E25 therapy and they will allow us to determine which allergic diseases as well aswhich patient populations will receive the most therapeutic benefit.>
| Gill, Michelle A; Bajwa, Gagan; George, Tiffany A et al. (2010) Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells. J Immunol 184:5999-6006 |
