THE HYPEREOSINOPHILIC SYNDROMES AND MEPOLIZUMAB

描述(由申请人提供)：术语，高嗜酸性粒细胞综合征(HES)，指的是一组血嗜酸性粒细胞升高的患者。在过去的二十年里，某些类别的患者被认为是HES亚组。例如，与嗜酸性粒细胞增多症相关的发作性血管水肿综合征、结节综合征、嗜酸性粒细胞增多症、风湿病、皮炎和肿胀、与T细胞克隆相关的HES以及骨髓增生性变异体已经被认识到。T细胞克隆产生TH2型细胞因子的患者显示出L-5的产生，而IL-5刺激骨髓产生和嗜酸性粒细胞的激活。美波利单抗是一种抗IL-5的高亲和力、特异性、人源化的单抗，能迅速清除外周血中的嗜酸性粒细胞。这种抗体已经用于包括哮喘在内的几种疾病的患者，而且它非常没有副作用。随附的核心临床方案描述了甲波利单抗治疗HES的试验；这一机械性建议试图了解甲波利单抗反应的基本机制。具体来说，我们将：1.确定美波利单抗是否调节T细胞的功能，包括它们的分化和细胞因子的产生。2.检测甲波利单抗治疗是否抑制嗜酸性粒细胞活化、细胞因子的产生及嗜酸性粒细胞表面IL-5受体的表达。3.确定甲波利单抗是否显示出迄今未被认识到的HES的异质性。总体而言，这是一个独特而史无前例的机会，可以进行一项多中心研究，让具有相当经验的研究人员参与，以调查抗IL-5治疗的效果，并确定哪些嗜酸性粒细胞激活的标志物与疾病活动性最相关。之前的研究大多来自单一机构，这将是第一次多中心研究。我们预计，通过确定基本上所有的HES亚型及其频率，通过确定抗IL-5改变HES免疫学基础的能力，通过识别和调查对抗IL-5无效的患者，通过确定可以用抗IL-5有效治疗的患者的特征，这些结果将为这种疾病带来新的曙光。

DESCRIPTION (provided by applicant): The term, hypereosinophilic syndromes (HES), refers a spectrum of patients with elevated blood eosinophils. Over the past two decades, certain categories of patients have been recognized as HES subgroups. For example, the syndromes of episodic angioedema associated with eosinophilia, the syndrome of nodules, eosinophilia, rheumatism, dermatitis and swelling, HES associated with T cell clones, and the myeloproliferative variant have been recognized. Patients with T cell clones producing TH2 cytokines show evidence of L-5 production and IL-5 stimulates bone marrow production and activation of eosinophils. Mepolizumab is a high-affinity, specific, humanized monoclonal antibody to IL-5 which rapidly depletes eosinophils from the peripheral blood. This antibody has been administered to patients with several diseases, including asthma, and it is remarkably free of side-effects. The accompanying core clinical protocol describes a trial of mepolizumab for the treatment of HES; this mechanistic proposal seeks to understand the basic mechanisms underlying the response to mepolizumab. Specifically, we will: 1. Determine whether mepolizumab modulates T-cell functions, including their differentiation and cytokine production. 2. Test whether mepolizumab treatment suppresses eosinophil activation, cytokine production and expression of the IL-5 receptor on the eosinophils of treated patients. 3. Determine whether mepolizumab reveals heterogeneity in HES not heretofore recognized. Overall, this is a unique and unprecedented opportunity to conduct a multicenter study involving investigators with considerable experience to investigate the effects of anti-IL-5 administration and to determine which markers of eosinophil activation are best correlated with disease activity. Previous studies have largely been from single institutions, and this will be the first multicenter study. We anticipate the results will shed new light on this disease by defining essentially all HES subtypes and their frequencies, by determining the ability of anti-IL-5 to alter the immunological bases of HES, by identifying and investigating patients not responsive to anti-IL-5 and by identifying the characteristics of patients who can be effectively treated with anti-IL-5.