Psoriatic lesional skin organ culture replicates therapeutic benefits and reveals short-term responses to IL-23 and IL-17A blockade

Summary: Abstract Body: The IL-23/IL-17 axis is crucial in psoriasis pathogenesis, and systemic blockade of IL-23 and IL-17A significantly improves clinical outcomes in moderate-to-severe patients. Here, we evaluated the suitability of the ex vivo full-thickness human psoriatic lesional and peri-lesional skin model as a tool to investigate drug efficacy and short-term responses. Histological analysis confirmed the preservation of the lesional psoriatic phenotype in serum-free medium cultured for 96h. Comparative RNAseq analysis between cultured lesional and peri-lesional samples revealed enrichment of psoriasis-related genes and pathways, e.g. T-cell activation, Th17 responses, and (hyper-)keratinization. Among others, increased secretion of ß-defensin-2, CCL20, IL-17A, TNFα, IFNγ, and IL-23 was detected in the medium of lesional compared to peri-lesional skin evaluated by LegendPlex or ELISA. Additionally, quantitative (immuno-)histomorphometry confirmed higher numbers of CD3+IL-17A+ T-cells and CD14-CD11c+ and CD14+CD11c- mononuclear phagocytes (MNPs) in lesional skin punches after 72h of culture. Systemic treatment ex vivo with αIL-17A (Secukinumab) or αIL-23 (Guselkumab surrogate) antibodies for 48h alleviated the transcriptomic lesional psoriatic phenotype (32% and 36% respectively). While IL-17A blockade did not lead to a reproducible decrease in cytokine/chemokine secretion, αIL-23 administration reduced secretion of IL-1β, CCL20, IL-23 and IL-17A. Furthermore, IL-23 neutralization reduced mRNA expression of IL23A, FCGR1A (CD64), CD40 and CD80 and intradermal CD3+IL-17A+ T-cells, CD14+CD11c- monocytes, as well activated (CD40+) and psoriatic-relevant (CD64+) CD14-CD11c+ and CD14+CD11c+ MNPs. Thus, our human psoriatic lesional skin model replicates clinical therapeutic responses and serves as an excellent pre-clinical tool for investigating psoriasis therapeutics, including topical applications. Lisa Zondler¹, Markus Fehrholz¹, Athanasios Tsianakas², Britta Bunselmeyer³, Ralf Ludwig¹, Janin Edelkamp¹, Marta Bertolini¹ 1. QIMA Life Sciences, QIMA Monasterium, Münster, Germany. 2. Fachklinik Bad Bentheim, Bad Bentheim, Germany. 3. KliFOs, Osnabrück, Germany. Epidermal Structure and Barrier Function