Determination of Cellular and Clinical Thresholds for IgE-Mediated Reactivity

而通过皮肤试验或体外试验检测过敏原特异性IgE是一种有用的标记 在过敏敏感性方面，特异性IgE水平和过敏反应之间的关系还远不清楚。在……里面 事实上，对于食物、药物、昆虫叮咬和吸入性过敏原，大多数研究都表明 特异性IgE水平和对过敏原暴露的反应类型或严重程度。缺乏这样的一种 这种关系可能是由于我们建议在临床和体外研究的各种因素所致 本项目中描述的研究。需要检验的一个中心假设是，特定过敏原的组合 免疫球蛋白E和总免疫球蛋白E水平，特别是这两项测量的比率，通过影响FceRI 占有率和密度决定了细胞和临床反应的门槛和可能性。这 假说部分是基于我们的团队和其他实验室了解到的IgE是如何 FDA批准的降低IgE抗体疗法，奥马珠单抗，调节嗜碱性粒细胞和肥大细胞 FceRI的反应性和表面密度。给定不同组织中肥大细胞的半衰期 与嗜碱性粒细胞相比，奥马珠单抗对肥大细胞的作用更慢， 我们建议检验这样一种假设，即食物引起的过敏反应和后期反应是嗜碱性的。 在头两周内通过皮肤、呼吸道和口服过敏原激发来应对， 几个月后，奥马珠单抗给药。我们还假设，负责 嗜酸性粒细胞向呼吸道晚期反应部位的运输涉及到IgE介导的 招募嗜碱性粒细胞，然后释放能够激活上皮趋化因子产生的介质 对嗜酸性粒细胞有选择性。作为这些努力的一部分，我们建议开发一种新的可靠的诊断测试 与核心B的同事合作测量自由血清总IgE水平。 目标是使用一种已获批准的抗lge抗体来扩展我们对免疫球蛋白E生物学及其临床相关性的了解。 抗体，奥马珠单抗，作为调节游离IgE水平的机械性工具。

While the detection of allergen-specific IgE, either by skin testing or in vitro assays, is a useful marker of allergic sensitivity, the relationship between specific IgE levels and allergic responses is far from clear. In fact, for food, drug, insect sting and inhalant allergens most studies have shown no relationship between the levels of specific IgE and type or severity of responses to allergen exposure. The lack of such a relationship may be due to a variety of factors that we propose to investigate in the clinical and ex vivo studies described in this project. A central hypothesis to be tested is that a combination of the allergen-specific IgE and total IgE levels, especially the ratio of these two measurements, by influencing FceRI occupancy and density, determines the threshold and likelihood for cellular and clinical reactivity. This hypothesis is based in part on what our group and other laboratories have learned about how IgE, and an FDA-approved IgE-lowering antibody therapy, omalizumab, regulates basophil and mast cell responsiveness and surface density of FceRI. Given the half-life of mast cells in different tissue compartments and the slower onset of action of omalizumab on mast cells compared to that for basophils, we propose to test the hypothesis that food-induced anaphylaxis and late phase responses are basophildependent responses by performing skin, airway and oral allergen challenge within the first two weeks, and after months, of omalizumab administration. We also hypothesize that mechanisms responsible for trafficking of eosinophils to sites of airway late phase responses involve IgE-mediated triggering of recruited basophils, which then release mediators capable of activating epithelial chemokine production selective for eosinophils. As part of these efforts, we propose to develop a new and reliable diagnostic test for the measurement of free total serum IgE levels in collaboration with colleagues in Core B. Our overall goal is to expand our knowledge of the biology of IgE and its clinical relevance using an approved anti-lgE antibody, omalizumab, as a mechanistic tool to modulate free IgE levels.