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：
8889194
负责人：
FRED Douglass FINKELMAN
金额：
$ 33.18万
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/8889194
关键词：
Affinity Allergic Allergic Reaction Allergic rhinitis Anaphylaxis Antigens Asthma Atopic Dermatitis Basophils Binding Blood Cells Cell membrane Characteristics Clinical Cytokine Receptors Dendritic Cells Developed Countries Disease Dose Engineering Excision Food Hypersensitivity Genetic Health Histamine H1 Receptors Histamine H2 Receptors Human IgE Immediate hypersensitivity Inbred BALB C Mice Individual Injection of therapeutic agent Interleukin-4 Life Mediating 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（由应用程序提供）：该翻译的提案采用快速脱敏的方法来开发一种安全，有效和快速的方法来抑制人IgE介导的疾病。我们已经可以通过每小时给所有抗原（AG）的小鼠安全，快速地将它们脱敏，从而将它们的剂量增加一倍，抗FCϵRIα单克隆抗体（MAB），从太小的剂量开始，无法引起临床反应。使用该方案用抗FCϵRIαMAB处理小鼠，该抗FCϵRIαMAB仅结合IgE不占据的FCϵRI：（1）快速诱导对IgE/FϵRI信号传导的短暂抑制；（2）即使在具有高血清IgE水平的小鼠中，也会慢慢去除所有肥大细胞膜FCϵRI和IgE。在小鼠中，我们的方法比用Ag快速脱敏的方法更安全，并且可以通过反复注射抗FCϵRIα mAb无限期地安全地保持。现在，我们将适应人类的这种方法，使其更快，甚至更安全。 AIM 1使用具有类似于我们抗小鼠FCϵRIαmAb的特征的抗人（HU）FCϵRIαMAB来脱敏：（1）表达HuFCϵRiα而不是小鼠FCϵRIα的Huige处理的转基因小鼠；（2）缺乏细胞因子接收器的免疫缺陷点头/SCID小鼠常见的？链，Express转基因HUSCF，HUIL-3和HUGM-CSF，已重组人脐带血细胞（这些小鼠分泌人类IgE并产生人类肥大细胞和嗜碱性细胞）。我们还修改了我们的脱敏方案，以使其与潜在的人类使用更兼容，通过皮下而不是腹膜内注射抗HUFCϵRIαMAB。 AIM 2通过使用可去除所有肥大细胞HUFCϵRI的市售MAB，与抗fufcϵRiα mAb脱敏，无论其IgE占用方式如何。我们还产生了具有该特性的mAb，以便我们可以在AIM 3中修改其结构。AIM3可以通过抗HufcϵRiα mAb来提高快速脱敏的安全性。我们进一步抑制了在快速脱敏过程中可能发生的任何临床反应：（1）抑制H1和H2受体；（2）抑制酪氨酸激酶SYK；（3）工程抗FCϵRIα mAb，以更加热烈的结合与抑制性受体FcγRIIB。这些目标的成功完成可以提供一种方法来安全，迅速防止所有FCϵRI介导的疾病。