Effect of anti-IL4Ra on the Host-Microbe Interface in Atopic Dermatitis

抗白介素4受体α对特应性皮炎宿主-微生物界面的影响 摘要： 特应性皮炎(AD)是最常见的炎症性皮肤病，影响着1500万美国人(最多 17%的儿童和10%的成人)，最严重的疾病通常发生在成人患者中。它是 以针对空气传播、食物和金黄色葡萄球菌抗原的Th2免疫反应为特征 上皮屏障和皮肤对金黄色葡萄球菌定植的敏感性。这些功能中的哪一个是 目前尚不清楚哪些是主要的，哪些是次要的。为了开始解决这个关键问题，我们有 提出了一种使用DUPILAMAB(抗IL4Rα)的干预性人体临床试验，DUPILMA是一种高效的生物制剂， 阻断规范的Th2细胞因子、IL-4和IL-13与其相关受体的结合。这将是一个 中重度AD患者的多中心、RDBPC(±皮肤金黄色葡萄球菌定植)。我们会 对具有和不具有金黄色葡萄球菌定植的等量AD受试者进行分层登记以解决问题 无论这些亚型在基线时是否不同，还是对Th2阻断的反应不同。我们的中心假设是 DUPILUMA治疗将使皮肤的生物失调、表皮生物学和皮肤免疫正常化 AD受试者的反应。我们预测被金黄色葡萄球菌定植的AD受试者将有更严重的缺陷 在皮肤屏障，先天免疫力，皮内接种反应降低，并将对 DUPILUMA治疗。这些假设是过去5年ADRN观测结果的自然演变- 十年了。具体地说，这项研究将1)确定DUPILUMA如何改变 表皮转录组，表皮脂质组学，微生物组和微生物转录组，免疫图谱 循环中的白细胞以及金黄色葡萄球菌在这些网络中的定植作用，2)表征这种影响 DUPILUMA对皮肤屏障功能和表皮天然免疫系统的影响，3)评价 DUPILUMA对皮肤接种的适应性免疫反应。总而言之，这是一种机械论的 对RFP高度敏感的研究，因为它利用一种新的安全的系统治疗剂来 在两个AD亚型中选择性地靶向高度相关的细胞因子，这样做将决定 利用最先进的技术，Th2细胞因子影响皮肤微生物区系、屏障和疫苗反应性 有一群令人兴奋的有才华和合作精神的调查人员，他们是各自领域的领导者。

Effect of Dupilumab (anti-IL4Rα) on the Host-Microbe Interface in Atopic Dermatitis Abstract: Atopic Dermatitis (AD) is the most common inflammatory skin disease, affecting 15 million Americans (up to 17% of children and 10% adults) with the most severe disease typically observed in adult patients. It is characterized by a Th2 immune response directed against airborne, food and S. aureus antigens, a leaky epithelial barrier and a susceptibility to cutaneous colonization with S. aureus. Which of these features is primary and which are secondary remains unclear. To begin to address this critical question we have proposed an interventional human clinical trial with dupilumab (anti-IL4Rα), a highly effective biologic that blocks the binding of the canonical Th2 cytokines, IL-4 and IL-13 to their relevant receptors. This will be a multicenter, RDBPC in adult patients with moderate-severe AD (± skin colonization with S. aureus). We will stratify enrollment with equal numbers of AD subjects with and without S. aureus colonization to address whether these subphenotypes differ at baseline or in response to Th2 blockade. Our central hypothesis is that dupilumab treatment will normalize the cutaneous dysbiosis, epidermal biology and cutaneous immune responses in AD subjects. We predict that AD subjects colonized with S. aureus will have more severe defects in skin barrier, innate immunity, reduced responses to intradermal vaccination and will be more responsive to dupilumab treatment. These hypotheses are a natural evolution of ADRN observations made over the past 5- 10 years. Specifically, this study will 1) identify how dupilumab alters the baseline interactions between the epidermal transcriptome, epidermal lipidomics, microbiome & microbial transcriptome, immunoprofile of circulating leukocytes and what role S. aureus colonization plays in these networks, 2) characterize the effect of dupilumab on skin barrier function and the epidermal innate immune system, 3) evaluate the effect of dupilumab on the adaptive immune response to cutaneous vaccination. In summary, this is a mechanistic study that is highly responsive to the RFP as it utilizes a novel and safe systemic therapeutic agent to selectively target highly relevant cytokines in two AD subphenotypes and in so doing will determine whether Th2 cytokines affect skin microbiota, barrier, and vaccine responsiveness utilizing state-of-the-art technologies with an exciting group of talented and collaborative investigators who are leaders in their field.