The Role of CD32 in the Basophil Response to Specific Immunotherapy

描述（由申请方提供）：嗜碱性粒细胞分泌介质是过敏反应的重要组成部分。这种分泌是如何被两种低亲和力IgG受体（CD32a和CD32b）调节的是本提案的重点。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为这种治疗方法的成功（或失败）提供了解释，但这些假设中的大多数都没有在人类中得到完全的检验。长期观察之一是，SIT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。该提议将检验阻断IgG通过细胞表面CD32b（FcgRIIb）对人嗜碱性粒细胞应答施加影响的假设。有限的现有文献测试这一假设是矛盾的，但有新的信息，可能有助于探讨这一点 质疑并解释SIT临床研究中可能发生的潜在生物学变异。本实验室的研究表明，CD32a和CD32b的相对比例可以随着细胞因子暴露而改变。该建议的第一个目的是扩展我们对CD32表达调控的认识，特别强调是否存在允许CD32a介导分泌的CD32a和CD32b基因型和IgG亚类谱。其中一些知识将用于进一步改进临床研究的设计和解释 这是该提案第二个目标中提出的。临床研究的目的是提供探索所提出的假设所需的患者，但我们将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激发测量的SIT临床结局相结合。第三个目标探索了一个独特的新观察，即通过CD32b调节IgE介导的嗜碱性粒细胞分泌允许抑制介质释放，但维持下调过程，如syk表达的丧失。这种情况可能为在一般人群中观察到的syk的重要可变表达提供了解释，现在已知这种变化与至少一种新的哮喘治疗药物奥马珠单抗的疗效有关。第三个目标将确定CD32b是否可以调节IgE介导的SYK表达下调从他们的CD34+祖细胞成熟的嗜碱性粒细胞，并检查这个过程的基础。

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.