Determination of Cellular and Clinical Thresholds for IgE-Mediated Reactivity

虽然通过皮肤测试或体外测定检测过敏原特异性IgE是过敏性鼻炎的有用标志物， 虽然过敏性反应的发生与特异性IgE水平有关，但特异性IgE水平与过敏反应之间的关系尚不清楚。在 事实上，对于食物、药物、昆虫叮咬和吸入性过敏原，大多数研究表明， 特异性IgE水平和过敏原暴露反应的类型或严重程度。缺乏这种 这种关系可能是由于各种因素，我们建议在临床和体外研究， 该项目中描述的研究。一个有待检验的中心假设是， IgE和总IgE水平，特别是这两种测量值的比值，通过影响FceRI 占据率和密度决定了细胞和临床反应性的阈值和可能性。这 这一假设部分是基于我们的团队和其他实验室已经了解到的关于IgE和一种 FDA批准的降低IgE抗体疗法奥马珠单抗可调节嗜碱性粒细胞和肥大细胞 FceRI的反应性和表面密度。鉴于肥大细胞在不同组织中的半衰期 与嗜碱性粒细胞相比，奥马珠单抗对肥大细胞的作用起效较慢， 我们建议检验食物引起的过敏反应和晚期反应是嗜碱性粒细胞依赖性的假说 通过在前两周内进行皮肤、气道和口腔过敏原激发， 以及数月后给予奥马珠单抗。我们还假设， 嗜酸性粒细胞向气道晚期反应部位的运输涉及IgE介导的 募集嗜碱性粒细胞，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的同事合作测量游离总血清IgE水平。我们的整体 我们的目标是扩大我们的知识的生物学IgE及其临床相关性使用批准的抗IgE 抗体奥马珠单抗作为调节游离IgE水平的机制工具。

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.