The Role of CD32 in the Basophil Response to Specific Immunotherapy

CD32 在嗜碱性粒细胞对特异性免疫治疗反应中的作用

• 批准号: 8482055
• 负责人: Donald W MacGlashan
• 金额: $ 32.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8482055
• 关键词: Accounting; Affinity; Allergens; Allergic Disease; Anaphylaxis; Antibodies; Antibody Affinity; Antigen Presentation; Antigens; Area; Basophils; Binding; Biological; Biology; Blocking Antibodies; CD32 Antigens; Cell surface; Cells; Clinical; Clinical Research; Clinical Trials; Data; Disease; Dose; Elements; Epitopes; Equilibrium; Event; Generations; Genetic Polymorphism; Genotype; Hand; Human; IgE; IgG Receptors; Immune; Immune response; Immunoglobulin G; Immunotherapy; In Vitro; Knowledge; Literature; Measurement; Measures; Mediating; Methods; Mus; Nose; Oral; Outcome; Pathway interactions; Patients; Phenotype; Production; Property; Publishing; Reaction; Regulation; Regulatory T-Lymphocyte; Relative (related person); Role; Route; Sampling; Signal Pathway; Signal Transduction; Skin; Techniques; Testing; Therapeutic; Time; Translating; Treatment Efficacy; Variant; Whole Blood; atopy; base; cytokine; design; improved; in vitro testing; in vivo; insight; interest; prevent; pyroglyphid; receptor; response; success

DESCRIPTION (provided by applicant): Specific immunotherapy (SIT) is a mainstay approach in the treatment of allergic diseases. While there are several strong hypotheses that provide an explanation for the success (or lack thereof) of this therapeutic approach, most of these hypotheses are incompletely examined in humans. One of the longstanding observations is that SIT induces enhanced production of specific IgG antibodies but the mechanism by which these antibodies may contribute to the efficacy of SIT is not well understood. This proposal will test th hypothesis that blocking IgG exerts an influence on the human basophil response through cell surface CD32b (FcgRIIb). The limited existing literature testing this hypothesis is contradictory but there is new information that may help to explore this question and account for potential biological variation that may occur in a clinical study of SIT. Preliminary studies in this laboratry demonstrate that the relative proportion of CD32a and CD32b can be altered with cytokine exposure. Existing literature is also ambiguous on the signal transduction mechanisms that may mediate CD32 effects. Therefore, the first aim of this proposal is to expand our knowledge of the regulation of CD32 expression and its signaling mechanisms. This knowledge will be used to further improve on the design and interpretation of a clinical study of SIT that is proposed in the second aim of the proposal. The purpose of the clinical study is to provide the patients needed to explore the proposed hypothesis but we will couple the results from the in vitro testing of basophil function to the clinical outcomes of SIT as measured by experimental nasal allergen challenges. The third aim sets out the in vitro testing that will be done during the clinical trial It will focus on several areas of basophil and CD32 biology; to enumerate the quantity and affinity of blocking IgG isotypes, to anchor the study with a traditional method of measuring blocking antibody effect, to introduce a new method to assess the contribution CD32 to the basophil response, to test the basophil for changes in its phenotype, especially as it relates to components of the CD32 signaling pathways and to enumerate the patients' CD32 genotype since it is now apparent that polymorphisms alter CD32 binding to IgG. It is expected that with this new information in hand, we will be able to demonstrate that CD32 participates in blocking antibody effect or understand why it does not.

描述（由申请人提供）：特异性免疫疗法（SIT）是治疗过敏性疾病的主要方法。虽然有几个强有力的假设可以解释这种治疗方法的成功（或缺乏），但这些假设中的大多数都没有在人类身上得到充分的检验。长期观察之一是 SIT 会诱导特异性 IgG 抗体的产生增强，但这些抗体可能有助于 SIT 功效的机制尚不清楚。该提案将验证阻断 IgG 通过细胞表面 CD32b (FcgRIIb) 对人类嗜碱性粒细胞反应产生影响的假设。测试这一假设的现有有限文献是相互矛盾的，但有新的信息可能有助于探索这个问题并解释 SIT 临床研究中可能发生的潜在生物学变异。该实验室的初步研究表明，CD32a 和 CD32b 的相对比例可以随着细胞因子暴露而改变。现有文献对于可能介导 CD32 效应的信号转导机制也含糊不清。因此，该提案的首要目的是扩展我们对 CD32 表达调控及其信号机制的了解。这些知识将用于进一步改进 SIT 临床研究的设计和解释，该研究在 该提案的第二个目标。临床研究的目的是为探索所提出的假设提供所需的患者，但我们将把嗜碱性粒细胞功能的体外测试结果与通过实验性鼻过敏原挑战测量的 SIT 临床结果结合起来。第三个目标规定了临床试验期间将进行的体外测试，重点是嗜碱性粒细胞和 CD32 生物学的几个领域；枚举阻断 IgG 同种型的数量和亲和力，用测量阻断抗体效果的传统方法来锚定研究，引入一种新方法来评估 CD32 对嗜碱性粒细胞反应的贡献，测试嗜碱性粒细胞表型的变化，特别是因为它与 CD32 信号通路的组成部分相关，并枚举患者的 CD32 基因型，因为现在很明显， 多态性改变 CD32 与 IgG 的结合。预计有了这些新信息，我们将能够证明 CD32 参与阻断抗体效应或了解为什么它不参与。