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Single cell analysis of clinically resolved epidermal skin from nickel-challenged individuals treated with either anakinra or placebo

ABSTRACT: Background: Topical corticosteroids are used as a standard treatment option in allergic contact dermatitis (ACD). However, the treatment doesn’t inhibit the generation of skin-resident memory T (TRM) cells. These cells play an important role in the pathogenesis of skin flare ups in ACD. Currently, findings in murine models suggest interleukin (IL)-1 inhibition can suppress the immune response to contact allergens. Objectives: To determine if IL-1 inhibition can attenuate acute skin flare-ups and restrict the development of TRM cells. Methods: A murine model was used to investigate the role of IL-1 on epidermal TRM cells by measuring changes in ear thickness and T cell composition. Next, we conducted a randomized, double-blinded, placebo-controlled trial (RCT) [H-22001652; EudraCT number: 2021-004750-39]. Nickel allergic participants were patch-tested at 1) baseline, 2) while being treated with either anakinra or placebo, 3) and 21 days after treatment. The primary outcome was the International Contact Dermatitis Research Group (ICDRG) score 48 hours after patch test application. While secondary outcomes were a reduction of immune cells in clinically cleared and actively inflamed skin. Results: In mice, IL-1 inhibition decreased the number of epidermal CD8+ TRM cells and attenuated skin flare-ups upon re-exposure. Twenty participants were enrolled and completed the RCT, but anakinra failed to improve ICDRG scores. Conclusions: Although IL-1 inhibition has been proven successful in murine models for ACD, there is currently no clinical evidence that suggest it being efficacious as a short-term treatment option for acute skin flare-ups in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250594 | GEO | 2026/04/28

REPOSITORIES: GEO

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Project description:The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in the CIAS1 gene that result in increased production and secretion of active IL-1≤. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bony growth plates, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n=14) before treatment [lesional (LS) and non-lesional (pre-NL) skin] and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®), to normal skin (n=5). Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c+ dermal dendritic cells and CD163+ macrophages expressed activated caspase-1 and are the likely sources of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3+ T cells and HLA-DR+ cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. Differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification are indicative of epigenetic modification in the various tissue states. Overall, the dysregulated genes and pathways suggest extensive “adaptive” mechanisms to control inflammation, and maintain tissue homeostasis in the skin of patients with NOMID. To determine the transcsriptome of skin samples in Neonatal-onset Multisystem Inflammatory Disease (NOMID), using pre-treatment non-lesional (pre-NL, n=4); lesional (LS, n=6); post-treatment non-lesional (post-NL, n=8), and normal skin (n=5). Comparison of mean gene expression of each group at baseline, and considering treatment effect

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Single cell analysis of clinically resolved epidermal skin from nickel-challenged individuals treated with either anakinra or placebo

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