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

项目摘要/摘要 阿司匹林加重的呼吸系统疾病(AERD)是一种慢性炎症综合征，影响14%的人 成人重度哮喘和30%的哮喘和慢性鼻窦炎合并鼻息肉 (CRSWNP)。AERD患者出现复发性鼻息肉，导致鼻塞、鼻窦疼痛和 完全丧失嗅觉。既不是持续炎症和息肉的最初原因，也不是驱动因素 再生是已知的，而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 治疗是一个重大的治疗进步，但IL-4Rα和IL-33/ST2信号在推动 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的病理生理学涉及到两者持续的功能异常 鼻息肉组织内的肥大细胞和上皮细胞，这有助于疾病的持久性， 复发和严重程度。这些细胞的失调是紧密相连的，并可能受到IL-4Rα的调节 和IL-33信号。该项目将确定IL-4Rα和IL-33/ST2信号在细胞中的特异性作用 导致慢性呼吸道炎症，困扰着AERD和鼻息肉患者。使用 强效IL-4Rα拮抗剂杜匹单抗的双盲、安慰剂对照平行设计试验 REGN3500，一种有效的IL-33抑制剂，我们将检验以下中央假设：(1)临床发作迅速 杜匹单抗抑制IL-4Rα对急性呼吸窘迫综合征的改善主要是由于药物的直接作用 在MC和EPC上；(2)REGN3500会迅速直接抑制MC的激活，但不起作用 直到它抑制IL-13的产生，因此在完全临床上将有更多的延迟发病 有效性。目的1确定DUPILUMA和REGN3500治疗AERD的疗效。目标2 将确定IL-4Rα和IL-33/ST2信号对肥大细胞、上皮细胞激活的相关性 功能障碍和AERD的呼吸道炎症。为了解决我们的假设，我们提出了以下建议 目标： 目的1.比较抗IL-4α(杜匹单抗)和抗IL-33(REGN3500)治疗慢性粒细胞白血病的临床疗效。 AERD患者鼻息肉的双盲、安慰剂对照临床试验。 目的2.通过联用确定抗IL-4Rα和抗IL-33对急性呼吸窘迫综合征的治疗作用的机制(S) 早期和晚期介质和效应细胞读数的变化对临床疗效的影响。

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.