The Role of CD32 in the Basophil Response to Specific Immunotherapy

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身上得到完全的检验。长期以来的观察之一是，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疗效的机制尚不清楚。这一提议将验证阻断IgG通过细胞表面CD32b （FcgRIIb）影响人嗜碱性粒细胞反应的假设。有限的现有文献验证这一假设是矛盾的，但有新的信息可能有助于探索这个问题，并解释可能发生在SIT临床研究中的潜在生物学变异。本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。现有文献对介导CD32作用的信号转导机制也不明确。因此，本提案的第一个目的是扩大我们对CD32表达调控及其信号传导机制的认识。这些知识将用于进一步改进临床研究的设计和解释

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.