Suppression of basophil activation by IgE glycovariants

IgE 糖变体抑制嗜碱性粒细胞活化

• 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
• 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

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.

项目总结