Immunotherapeutics For Allergic Diseases And Asthma

本项目旨在开发过敏性疾病的新型免疫疗法，以及了解其作用机制和合理应用所需的实验室技术。高剂量静脉注射免疫球蛋白（IVIG）被用作免疫治疗药物，已知可清除补体片段C3b和C4b。我们最近证明，除了这些已知的作用，IVIG中和C3a和C5a过敏毒素，这在过敏性疾病的病理生理中很重要。IVIG在体外以及在小鼠哮喘模型和猪过敏毒素诱导的心肺窘迫模型中阻断了这些过敏毒素的活性。这些结果证明了IVIG的一种新的治疗活性，并表明开发更特异性的C3a和C5a过敏毒素清除剂可能具有治疗潜力。

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.