CD23 Destabilization and IgE Regulation

CD23 不稳定和 IgE 调节

基本信息

批准号：
7476201
负责人：
DANIEL H CONRAD
金额：
$ 14万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7476201
关键词：
Address Affect Affinity Allergic Allergic rhinitis Animals Antibodies Area Asthma B-Lymphocytes Backcrossings Binding Biological Models Cell surface Cleaved cell Collaborations Data Disease Dominant-Negative Mutation Elevation Endopeptidases Eosinophilia Exhibits Follicular Dendritic Cells Genes Helminths Human IDEC-152 Monoclonal Antibody IgE IgE Receptors In Vitro Injection of therapeutic agent Kainic Acid Laboratories Lectin Lymphocyte Mediating Messenger RNA Metalloproteases Modeling Monoclonal Antibodies Mouse Strains Mus Natural Immunity Patients Peptide Hydrolases Pharmacologic Substance Phenotype Play Preparation Production Protein Overexpression Protocols documentation Publishing Rattus Reagent Regulation Relative (related person)Role Serum Severities Severity of illness Signal Transduction Signaling Molecule Small Interfering RNA Surface System Transgenic Animals Transgenic Mice Transgenic Organisms Wild Type Mouse Work aluminum sulfate atopy cell type chemokine concept cytokine disorder control extracellular improved in vivo inhibitor/antagonist interest mouse model response role model transcription factor

项目摘要

Current studies have indicated that antibodies directed against the stalk region of CD23 cause enhancement of IgE synthesis in both the human in vitro and mouse in vivo systems. CD23 transgenic mice, which overexpress CD23 on all lymphocytes and follicular dendritic cells, exhibit drastically reduced IgE production in both helminth and alum/Ag models. The data suggest a model where the role of CD23 is initially to serve as a component of innate immunity to signal for IgE production by becoming destabilized and cleaved, and later by its overexpression at the cell surface to downmodulate IgE production. This project will investigate the mechanism(s) of these effects. Aim#1 examines the mouse system where the destabilizing mAb 19G5 gives enhanced IgE synthesis in vivo. Importantly, the metalloprotease, ADAM10, has been identified as the primary CD23 sheddase in mouse and humans. The role of ADAM10 in allergic disease will be modeled by making transgenic mice that overexpress ADAM10 or make a dominant negative ADAM10. In addition, we will examine the mechanism for the 19G5-dependent enhancement of IgE production by investigating the association of CD23 with another negative signaling molecule, LAX, which has recently been shown to both modulate CD23 expression and regulate IgE levels. Aim#2 will investigate the affect of CD23 overexpression and CD23 destabilization on the mouse asthma model with respect to both modulation and exacerbation of disease. We will utilize both IgE and the new ADAM10 transgenics to evaluate the mechanism(s) of the suppression of eosinophilia as well as the capacity of CD23 to modulate the asthma phenotype. In addition, Lyn deficient mice will be used to evaluate the capacity of CD23 to modulate the extreme asthma phenotype. Aim#3 will investigate the human in vitro IgE synthesis models with respect to the mechanisms involved in IgE synthesis enhancement, seen with anti-stalk antibodies and synthesis suppression, seen with certain anti-lectin mAbs. The importance of ADAM10 in human CD23 cleavage and IgE production will also be explored as will the involvement of LAX. Finally, we will determine if IgE production by B cells obtained from normal and allergic subjects is affected differently by destabilization or stabilization of CD23. In summary, these studies examine the mechanism of action of a natural regulator of IgE production, CD23, with the objective of developing protocols to enhance CD23 expression and thereby diminish IgE production, and, by analogy, allergic diseases such as asthma in which IgE plays a dominant role.

目前的研究表明，针对 CD23 茎区的抗体会导致增强人类体外和小鼠体内系统中的 IgE 合成。 CD23 在所有淋巴细胞和滤泡树突细胞上过度表达 CD23 的转基因小鼠表现出蠕虫和明矾/Ag 模型中 IgE 的产生都大大减少。数据暗示了一个模型 CD23 的作用最初是作为 IgE 产生信号的先天免疫的一个组成部分通过变得不稳定和裂解，然后通过其在细胞表面的过度表达来下调 IgE 产生。该项目将研究这些影响的机制。目标#1 检查小鼠系统，其中不稳定的 mAb 19G5 增强体内 IgE 合成。重要的是，金属蛋白酶 ADAM10 已被确定为小鼠中主要的 CD23 脱落酶和人类。 ADAM10 在过敏性疾病中的作用将通过制作转基因小鼠来模拟 ADAM10 过度表达或 ADAM10 显性失活。此外，我们将检查通过研究 IgE 产生的 19G5 依赖性增强机制 CD23 与另一种负信号分子 LAX 最近被证明可以调节 CD23 表达并调节 IgE 水平。 Aim#2 将研究 CD23 过度表达的影响小鼠哮喘模型中 CD23 的不稳定与调节和恶化有关疾病。我们将利用 IgE 和新的 ADAM10 转基因来评估其机制抑制嗜酸性粒细胞增多以及 CD23 调节哮喘表型的能力。在此外，Lyn缺陷小鼠将用于评估CD23调节极端的能力哮喘表型。 Aim#3 将研究人类体外 IgE 合成模型参与 IgE 合成增强的机制，见抗茎抗体和合成抑制，见于某些抗凝集素单克隆抗体。 ADAM10 在人类 CD23 裂解中的重要性还将探讨 IgE 的生产以及洛杉矶国际机场的参与。最后，我们将确定 IgE 是否从正常受试者和过敏受试者获得的 B 细胞的产生受到不稳定的影响不同或CD23的稳定化。总之，这些研究探讨了天然药物的作用机制。 IgE 产生的调节因子 CD23，目的是开发增强 CD23 的方案表达，从而减少 IgE 的产生，以此类推，过敏性疾病，例如哮喘其中IgE起主导作用。