This project seeks to develop novel immunologic therapies for allergic diseases as well as the laboratory techniques required to understand their mechanisms of action and rational application. High dose intravenous immunoglobulin (IVIG) is used as an immunotherapeutic and is known to scavenge complement fragments C3b and C4b. We recently demonstrated that, in addition to these known effects, IVIG neutralizes the C3a and C5a anaphylatoxins, which are important in the pathophysiology of allergic diseases. IVIG blocked the activity of these anaphylatoxins in vitro as well as in both a mouse model of asthma and a porcine model of anaphylotoxin induced cardiopulmonary distress. These results demonstrate a novel therapeutic activity of IVIG and suggest that the development of more specific scavengers of the C3a and C5a anaphylatoxins may have therapeutic potential. We have completed a clinical trial examining the immunological effects of allergen immunotherapy by monitoring allergen specific T cell responses. The hypothesis of this work is that allergen immunotherapy works via tolerance (a decrease in allergen specific T cells) rather than via a Th2 to Th1 shift. Understanding the immunological mechanisms of allergen immunotherapy is a requisite for developing new more effective antigen specific therapies. Eosinophilic gastroenteritis is a severe inflammatory disease of the gut, characterized by dense tissue eosinophil infiltration and is often associated with atopy and food allergy. In these food allergic subjects, eosinophilic gastroenteritis appears to be a severe manifestation of food allergy and as such, provides a model system in which to examine questions relating to the pathogenesis of food allergy. To examine the role of IL-5 in subjects with eosinophilic gastroenteritis and food allergy, we performed a clinical trial using SCH55700, a humanized anti-IL-5 monoclonal antibody. A single dose of SCH55700 yielded a rapid 80% drop in peripheral blood eosinophil counts within 48 hours and that after one month gastrointestinal eosinophils were decreased by 50-70% in 3 of 4 subjects. These data demonstrate that both the peripheral blood and tissue eosinophilia found in EG are responsive to IL-5 blockade.
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