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

Dupilumab（抗IL 4 R α）对特应性皮炎患者宿主-微生物界面的影响 摘要： 特应性皮炎（AD）是最常见的炎性皮肤病，影响了1500万美国人（高达 17%的儿童和10%的成人），通常在成人患者中观察到最严重的疾病。是 其特征在于针对空气、食物和链球菌的Th 2免疫应答。金黄色葡萄球菌抗原 上皮屏障和对皮肤定植敏感性。金黄色。以下哪项功能是 哪些是原发性的，哪些是继发性的仍然不清楚。为了开始解决这个关键问题，我们有 提出了一项dupilumab（抗IL 4 R α）的干预性人体临床试验，dupilumab是一种高效的生物制剂， 阻断典型的Th 2细胞因子IL-4和IL-13与其相关受体的结合。这将是一 中重度AD成人患者的多中心、RDPPC（± S. aureus)具有良好的抗菌活性。我们将 分层入组，有和无S的AD受试者数量相等。金黄色葡萄球菌定植以解决 这些亚表型是否在基线或对Th 2阻断的应答中不同。我们的中心假设是 dupilumab治疗将使皮肤生态失调、表皮生物学和皮肤免疫正常化 AD受试者的反应。我们预测AD受试者与S.金黄色葡萄球菌将具有更严重的缺陷 在皮肤屏障、先天免疫中，对皮内接种的反应降低，对 dupilumab治疗。这些假设是过去5年ADRN观察结果的自然演变。 10年具体而言，本研究将1）确定dupilumab如何改变 表皮转录组学，表皮脂质组学，微生物组学和微生物转录组学，免疫分析 循环白细胞和S.金黄色葡萄球菌定植在这些网络中的作用，2）描述这种作用 dupilumab对皮肤屏障功能和表皮天然免疫系统的影响，3）评价dupilumab对皮肤屏障功能和表皮天然免疫系统的影响 dupilumab对皮肤接种获得性免疫应答的影响。总之，这是一种机械论的 对RFP高度响应的研究，因为其使用了一种新型安全的全身性治疗药物 选择性地靶向两种AD亚表型中高度相关的细胞因子，并且这样做将确定是否 Th 2细胞因子利用最新技术影响皮肤微生物群、屏障和疫苗反应性 与一群在各自领域处于领先地位的才华横溢、相互协作的研究人员一起工作。

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.