Immunotherapeutics For Allergic Diseases And Asthma

该项目旨在开发用于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）被用作免疫抑制剂，已知可抑制补体片段C3 b和C4 b。我们最近证明，除了这些已知的作用，IVIG中和C3 a和C5 a过敏毒素，这是重要的变态反应性疾病的病理生理。IVIG在体外以及在哮喘小鼠模型和葡萄球菌毒素诱导的心肺窘迫猪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，并表明开发更特异的C3 a和C5 a过敏毒素清除剂可能具有治疗潜力。 我们已经完成了一项临床试验，通过监测过敏原特异性T细胞反应来检查过敏原免疫疗法的免疫学效果。这项工作的假设是过敏原免疫疗法通过耐受性（过敏原特异性T细胞的减少）而不是通过Th 2向Th 1的转变起作用。了解过敏原免疫治疗的免疫学机制是开发新的更有效的抗原特异性治疗的必要条件。嗜酸性粒细胞性胃肠炎是一种严重的肠道炎症性疾病，以致密组织嗜酸性粒细胞浸润为特征，通常与特应性和食物过敏有关。在这些食物过敏受试者中，嗜酸性粒细胞性胃肠炎似乎是食物过敏的严重表现，因此，提供了一个模型系统，在其中检查与食物过敏的发病机制有关的问题。为了研究IL-5在嗜酸性粒细胞性胃肠炎和食物过敏受试者中的作用，我们使用人源化抗IL-5单克隆抗体SCH 55700进行了临床试验。SCH 55700单次给药后48小时内外周血嗜酸性粒细胞计数迅速下降80%，1个月后4名受试者中有3名胃肠道嗜酸性粒细胞下降50-70%。这些数据表明，在EG中发现的外周血和组织嗜酸性粒细胞增多对IL-5阻断有反应。

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.