THE HYPEREOSINOPHILIC SYNDROMES AND MEPOLIZUMAB

描述（由申请人提供）：高嗜酸性粒细胞综合征（HES）是指血液中嗜酸性粒细胞升高的患者。在过去的二十年中，某些类型的患者被认为是HES亚组。例如，与嗜酸性粒细胞增多症相关的偶发性血管性水肿综合征，结节、嗜酸性粒细胞增多症、风湿病、皮炎和肿胀综合征，与T细胞克隆相关的HES，以及骨髓增生性变异体已被确认。产生TH2细胞因子的T细胞克隆患者显示出L-5产生的证据，IL-5刺激骨髓产生和嗜酸性粒细胞的激活。Mepolizumab是一种高亲和力、特异性、人源化的IL-5单克隆抗体，可快速清除外周血中的嗜酸性粒细胞。这种抗体已被用于包括哮喘在内的几种疾病患者，而且它明显没有副作用。伴随的核心临床方案描述了一项mepolizumab治疗HES的试验；这一机制建议旨在了解对mepolizumab反应的基本机制。具体来说，我们将：1。确定mepolizumab是否调节t细胞功能，包括它们的分化和细胞因子的产生。2. 检测mepolizumab治疗是否抑制治疗患者嗜酸性粒细胞活化、细胞因子产生和IL-5受体的表达。3. 确定mepolizumab是否揭示了迄今为止尚未认识到的HES异质性。总的来说，这是一个独特的和前所未有的机会，开展一项多中心研究，涉及具有丰富经验的研究人员，研究抗il -5给药的影响，并确定嗜酸性粒细胞激活的哪些标记与疾病活动最相关。以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，通过定义所有HES亚型及其频率，通过确定抗il -5改变HES免疫基础的能力，通过识别和调查对抗il -5无反应的患者，以及通过识别可以有效治疗的患者的特征，这些结果将为这种疾病提供新的视角。

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.