The Role of CD32 in the Basophil Response to Specific Immunotherapy

描述（由申请人提供）：嗜碱性细胞分泌介质是过敏反应的重要组成部分。两种低亲和力的IgG受体（CD32a和CD32b）如何调节这种分泌是本研究的重点。特异性免疫治疗（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。有限的现有文献测试这一假设是矛盾的，但有新的信息可能有助于探索这一点

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.