Project 3. Mechanisms of benefit of biologic agents for patients with aspirin-exacerbated respiratory disease (AERD)

项目总结/摘要 阿司匹林加重的呼吸道疾病（AERD）是一种慢性炎症综合征， 严重哮喘的成年人，以及30%的哮喘和慢性鼻窦炎伴鼻息肉的成年人 （CRSwNP）。AERD患者会出现复发性鼻息肉，导致鼻阻塞，鼻窦疼痛， 嗅觉完全丧失。既不是最初的原因，也不是持续炎症和息肉的驱动因素 再生是已知的，并且几乎没有有效的治疗方法。新开发的生物抗2型细胞因子 IL-4 R α和IL-33/ST 2信号转导在驱动免疫应答中的作用， 困扰哮喘、CRSwNP和AERD患者的慢性呼吸道炎症尚不清楚。 我们的初步数据表明，AERD的病理生理学涉及持续异常的功能， 鼻息肉组织内的肥大细胞和上皮细胞，这有助于疾病的持续， 复发和严重程度。这些细胞的失调与IL-4 R α密切相关，并可能受到IL-4 R α的调节。 和IL-33信号传导。本项目将确定IL-4 R α和IL-33/ST 2信号转导在细胞内的特异性作用， 导致AERD和鼻息肉病患者的慢性呼吸道炎症。使用 dupilumab（一种强效IL-4 R α拮抗剂）的双盲、安慰剂对照平行设计试验，和 REGN 3500是一种有效的IL-33抑制剂，我们将检验以下中心假设：（1）临床快速发作 dupilumab在AERD中的IL-4 R α抑制作用提供的改善主要归因于药物的直接作用 （2）REGN 3500将快速直接抑制MC活化，但不会影响 EpCs，直到它抑制IL-13的产生，并因此将具有更延迟的发作，用于完全的临床治疗。 有效性目的1将确定dupilumab和REGN 3500治疗AERD的疗效。目的2 将确定IL-4 R α和IL-33/ST 2信号传导对肥大细胞活化、上皮细胞活化和细胞增殖的相关性。 功能障碍和AERD中的呼吸道炎症。为了解决我们的假设，我们提出以下建议 目的： 目标1.比较抗IL-4α（dupilumab）和抗IL-33（REGN 3500）治疗以下疾病的临床疗效 鼻息肉的AERD在双盲，安慰剂对照的临床试验。 目标2.通过将抗IL-4 R α和抗IL-33诱导的AERD治疗获益联系起来，确定抗IL-4 R α和抗IL-33诱导的AERD治疗获益的机制 早期和后期的介质和效应细胞读数变化与临床疗效的关系。

PROJECT SUMMARY/ABSTRACT Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory syndrome that affects 14% of adults with severe asthma, and 30% of adults with asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Patients with AERD develop recurrent nasal polyps that cause nasal blockage, sinus pain, and complete loss of sense of smell. Neither the initial cause nor the driver of ongoing inflammation and polyp regrowth are known, and there are few effective therapies. Newly developed biologic anti-type 2 cytokine therapies are a significant treatment advance, but the roles of IL-4Rα and IL-33/ST2 signaling in driving the chronic respiratory inflammation that plagues patients with asthma, CRSwNP, and AERD are not known. Our preliminary data show that AERD pathophysiology involves persistently abnormal functions of both mast cells and epithelial cells within the nasal polyp tissue, which contributes to disease persistence, recurrence and severity. The dysregulation of these cells is tightly linked and potentially regulated by IL-4Rα and IL-33 signaling. This Project will determine the cell-specific roles of IL-4Rα and IL-33/ST2 signaling in driving the chronic respiratory inflammation that plagues patients with AERD and nasal polyposis. Using a double-blind, placebo-controlled parallel-design trial of dupilumab, a potent IL-4Rα antagonist, and REGN3500, a potent IL-33 inhibitor, we will test the central hypotheses that (1) the rapid onset of clinical improvement provided by IL-4Rα inhibition with dupilumab in AERD is due largely to the drug’s direct effects on both MCs and EpCs; and (2) REGN3500 will rapidly and directly suppress MC activation, but will not effect EpCs until it inhibits IL-13 production, and therefore will have a more delayed onset for full clinical effectiveness. Aim 1 will determin the efficacy of dupilumab and REGN3500 as treatments for AERD. Aim 2 will determine the relevance of IL-4Rα and IL-33/ST2 signaling on on mast cell activation, epithelial cell dysfunction, and the respiratory inflammation in AERD. To address our hypotheses, we propose the following Aims: Aim 1. Compare the clinical efficacy of anti-IL-4α (dupilumab) and anti-IL-33 (REGN3500) as treatments for nasal polyps in AERD in a double-blind, placebo-controlled clinical trial. Aim 2. Define the mechanism(s) of anti-IL-4Rα and anti-IL-33-induced therapeutic benefit in AERD by linking early and later changes in mediator and effector cell readouts to clinical efficacy.