Mechanistic Analysis of Anti-IgE Therapy of Asthma

在市中心的儿科医生中，哮喘的发病率和死亡率高得不成比例。 与其他儿科人群进行比较。在过去的几年里，内城哮喘研究 (ICAS)小组关注了可能导致这种健康差距的各种潜在因素。研究到 数据显示，大多数患有哮喘的市中心儿童对一些室内环境敏感 过敏原。然而，虽然已知免疫球蛋白E介导的免疫反应在过敏中起着重要作用 包括过敏性哮喘在内的疾病，这种高度过敏原在这个市中心的临床相关性 目前还不清楚人口情况。为了更好地了解IgE抗体在变态反应中的作用 哮喘，将进行一项使用人源化小鼠抗LGE单抗RhuMab-E25的治疗试验 在7个ICAS站点中有6个在市中心哮喘儿童中进行了宣传。拟议的机械论研究将寻求 阐明RhuMab-E25治疗临床疗效的免疫调节机制。这位代理 已被证明可以调节嗜碱性粒细胞和肥大细胞的功能，并抑制晚期哮喘 人类的应答和可能的B细胞IgE合成。此外，抗LGE的单抗对小鼠的治疗可导致 改变了Th2细胞因子谱。这些发现表明，IgE在协调复合体中发挥着重要作用 哮喘中发生的炎症事件以及RhuMab-E25可能作用于多种效应细胞。在 在机械论研究方面，我们将解决三个具体目标。具体来说，我们将：a)确定是否有 最高的尘螨和/或蟑螂特异性IgE水平将展示RhuMab的最大临床益处。 E25治疗；b)确定RhuMab-E25治疗是否会导致变应原驱动的Th2细胞因子产生减少 并增加患者外周血单个核细胞产生Th1细胞因子；以及c)确定 与IgE合成和/或功能相关的基因多态是导致 对RhuMab-E25治疗的反应。这些研究将使我们能够更好地理解细胞和分子 与RhuMab-E25治疗相关的事件，它们将使我们能够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收益。 &gt；

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 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-lgE 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-lgE 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. >