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: 8628227
• 负责人: Donald W MacGlashan
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628227
• 关键词: Accounting; Address; Affinity; Allergen Immunotherapy; Allergens; Allergic Disease; Anaphylaxis; Antibodies; Antigen Presentation; Antigens; Asthma; Basophils; Biological; Biology; Blocking Antibodies; Blood; CD32 Antigens; CD34 gene; Cell surface; Cells; Clinical; Clinical Research; Coupled; Dose; Down-Regulation; Equilibrium; General Population; Generations; Genetic Polymorphism; Genotype; Heterogeneity; Human; IgE; IgG Receptors; Immune; Immune response; Immunoglobulin G; Immunotherapy; Knowledge; Laboratories; Link; Literature; Maintenance; Measures; Mediating; Mediator of activation protein; Methods; Mus; Nose; Oral; Outcome; Pathway interactions; Patients; Phenotype; Play; Process; Production; Publishing; Reaction; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research Design; Role; Route; Skin; Source; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; Up-Regulation; Update; Variant; Work; allergic response; base; clinical efficacy; cytokine; design; improved; in vitro testing; insight; omalizumab; prevent; progenitor; public health relevance; receptor; receptor expression; response; success

DESCRIPTION (provided by applicant): Secretion of mediators from basophils is an important component of the allergic response. How this secretion is regulated by two low affinity IgG receptors (CD32a and CD32b) is the focus of this proposal. 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 the 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. Studies in this laboratory demonstrate that the relative proportion of CD32a and CD32b can be altered with cytokine exposure. The first aim of this proposal is to expand our knowledge of the regulation of CD32 expression, with a particular emphasis on whether there are genotypes of CD32a and CD32b and IgG subclass profiles that allow for CD32a-mediated secretion. Some of 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 explores a unique new observation that regulation of IgE-mediated secretion from basophils by CD32b allows for suppression of mediator release but maintenance of down-regulatory processes such as the loss in the expression of syk. This circumstance may provide an explanation for the important variable expression of syk seen in the general population, variation that is now known to be linked to the efficacy of at least one new asthma therapeutic, omalizumab. The third aim will determine whether CD32b can modulate the IgE-mediated down-regulation of syk expression in basophils maturing from their CD34+ progenitors and examine the basis for this process.

描述（由申请人提供）：从嗜碱性粒细胞中的介体的分泌是过敏反应的重要组成部分。该提议的重点是如何受到两个低亲和力IgG受体（CD32A和CD32B）调节该分泌的重点。特异性免疫疗法（SIT）是治疗过敏性疾病的主要方法。尽管有几种强有力的假设为这种治疗方法提供了成功（或缺乏成功）的解释，但这些假设中的大多数在人类中都无法完全研究。长期以来的观察之一是，SIT诱导特定IgG抗体的产生增强，但是这些抗体可能有助于SIT的功效的机制尚不清楚。该建议将检验以下假设：阻止IgG通过细胞表面CD32B（FCGRIIB）对人嗜碱性粒细胞反应产生影响。有限的现有文献检验该假设是矛盾的，但是有新的信息可能有助于探索这一点 问题并说明了SIT临床研究中可能发生的潜在生物学变异。该实验室的研究表明，通过细胞因子的暴露可以改变CD32A和CD32B的相对比例。该提案的第一个目的是扩大我们对CD32表达的调节的了解，特别是特别强调是否有CD32A和CD32B和IgG亚类概况的基因型可以允许CD32A介导的分泌。其中一些知识将用于进一步改善临床研究的设计和解释 提案的第二个目标中提出的SIT。临床研究的目的是为探索拟议假设所需的患者提供所需的患者，但我们将通过实验性鼻腔过敏原挑战来衡量的嗜碱性粒细胞功能的体外测试结果与SIT的临床结果相结合。第三个目标探讨了一个独特的新观察结果，即通过CD32B对Basophils对IgE介导的分泌进行调节，可以抑制介体释放，但维持下调过程，例如SYK表达的损失。这种情况可能会为SYK在一般人群中看到的重要变量表达提供一个解释，而现在已知与至少一种新的哮喘治疗性，粘胶蛋白单抗的疗效有关的变异。第三个目的将确定CD32B是否可以调节从其CD34+祖细胞成熟的粒细胞中IgE介导的Syk表达下调，并检查此过程的基础。