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Suppression of IgE-Mediated Disease by Polyclonal Rapid Desensitization

通过多克隆快速脱敏抑制 IgE 介导的疾病

基本信息

批准号：
9098577
负责人：
FRED Douglass FINKELMAN
金额：
$ 43.23万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098577
关键词：
Affinity Allergic Allergic Reaction Allergic rhinitis Anaphylaxis Antigens Asthma Atopic Dermatitis Basophils Binding Blood Cells Cells Characteristics Clinical Cytokine Receptors Dendritic Cells Developed Countries Disease Dose Engineering Excision FCGR2B gene Food Hypersensitivity Genetic Health Histamine H1 Receptors Histamine H2 Receptors Human IgE Immediate hypersensitivity Inbred BALB C Mice Individual Injection of therapeutic agent Interleukin 2 Receptor Gamma Interleukin-4 Life Mediating Membrane Modification Monoclonal Antibodies Mus NOD/SCID mouse Personal Communication Platelet-Derived Growth Factor Process Property Protein Tyrosine Kinase Protocols documentation Publishing Reaction Safety Serum Shock Signal Transduction Signaling Molecule Structure T-Lymphocyte Therapeutic Time Transgenes Transgenic Mice Transgenic Organisms Umbilical Cord Blood Urticaria Work allergic response anti-IgE aqueous cell type crosslink desensitization macrophage mast cell natural hypothermia novel therapeutic intervention omalizumab prevent rapid technique receptor reconstitution rectal research study response

项目摘要

DESCRIPTION (provided by applicant): This translational proposal uses a rapid desensitization approach to develop a safe, effective and rapid way to suppress human IgE-mediated disease. We can already safely, rapidly desensitize mice to all antigens (Ags) by injecting them hourly with doubling doses of an anti-FcϵRIα monoclonal antibody (mAb), starting with a dose too small to elicit a clinical reaction. Using this protocol to treat mice with an anti-FcϵRIα mAb that only binds FcϵRI that is not occupied by IgE: (1) rapidly induces short-lived suppression of IgE/FϵRI signaling; and (2) slowly removes all mast cell membrane FcϵRI and IgE, even in mice that have high serum IgE levels. In mice, our approach is safer than rapid desensitization with Ag and can safely be maintained indefinitely by repeated injection of anti-FcϵRIα mAb. We will now adapt this approach to humans, make it more rapid, and make it even safer. Aim 1 uses an anti-human (hu) FcϵRIα mAb that has characteristics similar to our anti-mouse FcϵRIα mAb to desensitize: (1) huIgE-treated transgenic mice that express huFcϵRIα instead of mouse FcϵRIα; and (2) immunodeficient NOD/SCID mice that lack the cytokine receptor common ? chain, express transgenic huSCF, huIL-3, and huGM-CSF and have been reconstituted with human cord blood cells (these mice secrete human IgE and generate human mast cells and basophils). We also modify our desensitization protocol to make it more compatible with potential human use by injecting anti-huFcϵRIα mAb subcutaneously instead of intraperitoneally. Aim 2 accelerates desensitization with antihuFcϵRIα mAb by using a commercially available mAb that removes all mast cell huFcϵRI, regardless of its IgE occupancy. We also generate our own mAb that has this property so that we can modify its structure in Aim 3. Aim 3 increases the safety of rapid desensitization with anti-huFcϵRIα mAb. We further suppress any clinical reactions that might occur during rapid desensitization by: (1) inhibiting H1 and H2 receptors; (2) inhibiting the tyrosine kinase syk; and (3) engineering anti-FcϵRIα mAb to bind more avidly to the inhibitory receptor, FcγRIIb. Successful completion of these aims could provide a way to safely and rapidly protect against all FcϵRI-mediated disease.

描述（由申请人提供）：本转化提案使用快速脱敏方法开发一种安全、有效和快速的方法来抑制人类ige介导的疾病。我们已经可以通过每小时给小鼠注射两倍剂量的anti-FcϵRIα单克隆抗体（mAb）来安全、快速地使小鼠对所有抗原（Ags）脱敏，开始时的剂量太小，不足以引起临床反应。使用该方案，使用仅结合未被IgE占用的FcϵRI的anti-FcϵRIα单抗治疗小鼠：(1)快速诱导IgE/FϵRI信号的短期抑制；(2)缓慢去除所有肥大细胞膜FcϵRI和IgE，即使在血清IgE水平高的小鼠中也是如此。在小鼠中，我们的方法比用Ag快速脱敏更安全，并且可以通过重复注射anti-FcϵRIα mAb安全地无限期维持。现在，我们将把这种方法应用于人类，使其更快，更安全。Aim 1使用具有与我们的抗小鼠FcϵRIα单抗相似特性的抗人（hu） FcϵRIα单抗来脱敏：(1)表达huFcϵRIα而不是小鼠FcϵRIα的经过巨量基因处理的转基因小鼠；(2)缺乏细胞因子受体的NOD/SCID免疫缺陷小鼠