Suppression of basophil activation by IgE glycovariants

IgE 糖变体抑制嗜碱性粒细胞活化

基本信息

批准号：
9900056
负责人：
Theodore S Jardetzky
金额：
$ 33.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900056
关键词：
Affect Affinity Allergens Allergic Allergic Disease Allergic Reaction Anaphylaxis Animal Model Antibodies Basophils Binding Carbohydrates Cell Culture Techniques Cell Line Cell Surface Receptors Cells Chronic Complex Data Effector Cell Engineering Extrinsic asthma Family Human Hypersensitivity ITIM IgE IgE Receptors Immune system Immunology In Vitro Incidence Inflammatory Inflammatory Response Laboratories Ligation Link Location Mediating Modification Molds Molecular Mus Pathway interactions Patients Play Pollen Polysaccharides Role Route Signal Transduction Site Structure Surface Testing Therapeutic antibodies Transgenic Mice Urticaria Variant allergic response base carbohydrate structure dander design glycosylation in vivo inhibitor/antagonist insight mast cell member mutant novel omalizumab pyroglyphid receptor recruit response sialic acid binding Ig-like lectin structural biology

项目摘要

Project Summary Most allergic reactions are caused by immunoglobulin E (IgE) antibodies that are specific for allergens and trigger potent inflammatory responses mediated by mast cells and basophils. IgE binds to the high affinity receptor (FcεRI) expressed on these allergic effector cells, making this a key interaction that is common to many different allergen-specific responses. The anti-IgE therapeutic antibody (Omalizumab) is currently used to treat allergic asthma and chronic idiopathic urticaria in patients. We determined the structure of the Omalizumab Fab bound to the IgE-Fc, clarifying how Omalizumab blocks IgE interactions with both receptors. We also designed an IgE-Fc glycosylation mutant that does not bind Omalizumab, but retains interactions with high and low affinity IgE receptors. This IgE glycovariant can be co-administered with Omalizumab, to replace the cell-bound IgE, exchanging allergen-reactive IgE with a non-reactive variant. This co-treatment of cells provides synergistic inhibition that is more potent at blocking basophil activation than either inhibitor alone. Our IgE glycovariant, which incorporates a single additional N-linked glycosylation site into the IgE-Fc, also shows more potent inhibition of basophils on its own as compared to the wild type IgE-Fc. The inhibition does not require direct competition for FceRI binding by “allergic” IgE. We hypothesize that carbohydrate-specific inhibitory receptors, such as members of the Siglec family, may be engaged by the IgE glycovariant to block FcεRI signaling. In this proposal, we will explore the impact of IgE glycosylation on the inhibition of human basophil activation, both with and without concomitant Omalizumab treatment, and identify the mechanisms by which IgE glycovariants suppress FceRI-dependent activation of allergic inflammatory cells.

项目概要大多数过敏反应是由对过敏原具有特异性的免疫球蛋白 E (IgE) 抗体引起的触发由肥大细胞和嗜碱性粒细胞介导的强效炎症反应。受体 (FcεRI) 在这些过敏效应细胞上表达，使其成为过敏反应中常见的关键相互作用目前使用抗 IgE 治疗抗体（奥马珠单抗）。治疗过敏性哮喘和慢性特发性荨麻疹患者我们确定了其结构。奥马珠单抗 Fab 与 IgE-Fc 结合，阐明了奥马珠单抗如何阻断 IgE 与两种受体的相互作用。我们还设计了一种 IgE-Fc 糖基化突变体，它不结合奥马珠单抗，但保留了与奥马珠单抗的相互作用。高亲和力和低亲和力 IgE 受体。该 IgE 糖变体可与奥马珠单抗共同给药，以替代奥马珠单抗。细胞结合的 IgE，将过敏原反应性 IgE 与非反应性变体交换。提供协同抑制作用，比单独使用任一抑制剂更有效地阻止嗜碱性粒细胞活化。 IgE 糖变体将一个额外的 N 连接糖基化位点整合到 IgE-Fc 中，还显示与野生型 IgE-Fc 相比，其对嗜碱性粒细胞的抑制更有效。需要与“过敏”IgE 直接竞争 FceRI 结合。抑制性受体，例如 Siglec 家族的成员，可能会被 IgE 糖变体参与以阻断在本提案中，我们将探讨 IgE 糖基化对人类抑制的影响。嗜碱性粒细胞激活，无论是否同时接受奥马珠单抗治疗，并通过以下方式确定机制：其中 IgE 糖变体抑制过敏性炎症细胞的 FceRI 依赖性激活。