Mechanistic Analysis of Anti-IgE Therapy of Asthma

描述(申请人提供)：哮喘的发病率和死亡率 被发现在市中心的儿科人口中不成比例地高 与其他儿科人群相比。在过去的几年里，内部 城市哮喘研究(ICAS)小组专注于各种潜在因素 这可能是造成这种健康差距的原因。迄今为止的研究表明， 大多数患有哮喘的市中心儿童对一些 室内环境过敏原。然而，虽然免疫球蛋白E介导的免疫反应 已知在包括过敏在内的过敏性i疾病中起重要作用。 哮喘，这种高度过敏原在临床上的相关性 这些市中心的人口目前还不清楚。为了更好地 了解IgE抗体在过敏性哮喘治疗中的作用 用人源化小鼠抗IgE单抗RhuMab-E25进行试验，将 由7个ICAS站点中的6个在市中心哮喘儿童中开展。这个 拟议的机制研究将寻求阐明免疫调节作用 RhuMab-E25治疗临床疗效的机制。这位代理 已被证明可以同时调节嗜碱性粒细胞和肥大细胞的功能，并抑制 人类哮喘晚期反应及可能的B细胞IgE合成。 此外，对小鼠的单抗IgE治疗会导致Th2的改变 细胞因子图谱。这些发现表明，IgE在人类免疫缺陷中起重要作用 协调发生在哮喘中的复杂炎症事件 RhuMab-E25可作用于多个效应细胞。在机理研究中，我们 将解决三个具体目标。具体而言，我们将：a)确定是否 尘螨和/或蟑螂特异性免疫球蛋白E水平最高的儿童 将展示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Th2减少 患者外周血细胞因子的产生及Th1细胞因子的增加 以及c)确定相关基因的多态是否 与IgE合成和/或功能有关的基因 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 它们将让我们确定哪些过敏性疾病以及哪些 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.