Effect of Dupilumab (anti-IL4R?) 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-IL4R?), 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.
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