Mechanistic Analysis of Anti-IgE Therapy of Asthma

描述（由申请人提供）：哮喘的发病率和死亡率 在市中心的儿科人群中， 与其他儿科人群相比。在过去的几年里， 城市哮喘研究（ICAS）小组关注各种潜在因素 可以解释这种健康差异。迄今为止的研究表明， 大多数患有哮喘的城市儿童对一些 室内环境过敏原然而，尽管IgE介导的免疫应答 已知在过敏性疾病I中起重要作用，包括过敏性 哮喘，这种高度过敏原敏感性的临床相关性， 目前还不清楚这一内城人口。为了更好 了解IgE抗体在过敏性哮喘中的作用， 使用人源化鼠单克隆抗IgE抗体RhuMab-E25的试验将 7个ICAS站点中的6个在市中心哮喘儿童中进行。的 提出的机制研究将试图阐明免疫调节 RhuMab-E25治疗的临床效果的潜在机制。此代理 已显示调节嗜碱性粒细胞和肥大细胞功能， 晚期哮喘反应和可能的人类B细胞IgE合成。 此外，小鼠的单克隆抗IgE治疗导致Th 2改变， 细胞因子谱。这些发现表明，IgE发挥了重要作用， 协调哮喘中发生的复杂炎症事件， RhuMab-E25可作用于多种效应细胞。在机械研究中，我们 将实现三个具体目标。具体而言，我们将：a）确定是否 尘螨和/或蟑螂特异性IgE水平最高的儿童 将证明来自RhuMab-E25疗法的最大临床益处; B） 确定RhuMab-E25治疗是否会导致过敏原驱动的Th 2减少 患者外周血细胞因子产生和Th 1细胞因子产生增加 血液单核细胞;以及c）确定是否与基因多态性相关的基因中的多态性。 与IgE合成和/或功能的个体差异负责， 对RhuMab-E25治疗的反应。这些研究将使我们能够更好地 了解与RhuMab-E25治疗相关的细胞和分子事件 它们能让我们确定哪些过敏性疾病 患者群体将获得最大的治疗益处。

DESCRIPTION (provided by applicant): Morbidity and mortality from asthma have been found to be disproportionately high in the inner-city pediatric population compared to other pediatric populations. Over the last several years, the Inner City Asthma Study (ICAS) group has focused on a variety of potential factors that may account for this health disparity. Studies to date indicate that the majority of inner-city children with asthma are sensitized to a number of indoor environmental allergens. However, while IgE-mediated immune responses are known to play an important role in allergic I diseases, including allergic asthma, the clinical relevance of this high degree of allergen sensitivity in this inner-city population currently is not clearly known. In order to better understand the role played by IgE antibodies in allergic asthma, a therapeutic trial using RhuMab-E25, a humanized murine monoclonal anti-IgE antibody, will be carried out in inner-city asthmatic children by 6 of the 7 ICAS sites. The proposed mechanistic studies will seek to elucidate the immunomodulatory mechanisms underlying the clinical effects of RhuMab-E25 therapy. This agent has been shown to modulate both basophil and mast cell function and to suppress the late-phase asthmatic response and possibly B cell IgE synthesis in humans. In addition, monoclonal anti-IgE treatment of mice leads to altered Th2 cytokine profiles. These findings indicate that IgE plays a major role in orchestrating the complex inflammatory events that occur in asthma and that RhuMab-E25 may act on multiple effector cells. In the mechanistic studies, we will address three specific aims. Specifically, we will: a) determine if children who have the highest dust mite-and/or cockroach-specific IgE levels will demonstrate the most clinical benefit from RhuMab-E25 therapy; b) determine if RhuMab-E25 therapy will lead to decreased allergen-driven Th2 cytokine production and increased Th1 cytokine production by patient peripheral blood mononuclear cells; and c) determine if polymorphisms in genes associated with IgE synthesis and/or function are responsible for individual variation in response to RhuMab-E25 therapy. These studies will allow us to better understand the cellular and molecular events associated with RhuMab-E25 therapy and they will allow us to determine which allergic diseases as well as which patient populations will receive the most therapeutic benefit.