661 Cell therapy trial of ectopic fibroblasts to modify skin identity

Abstract

Current therapeutic options for atopic dermatitis (AD) consist of either broad or targeted immunosuppressive agents. However, the natural course of AD can hardly be modified, as the disease invariably returns after cessation of treatment. Tissue-resident memory T-cells are hypothesized to be relevant players in mediating disease-specific 'immune memory', but their exact immunopathological phenotype is so far unknown. By using a multi-omics approach involving single-cell RNA sequencing combined with multiplex proteomics of skin samples, we studied AD patients undergoing short (16 weeks) and long-term (one year) treatment with the IL-4Ra blocker dupilumab. IL-4Ra blockade resulted in clearance of disease, decrease in skin immune cell counts, and normalization of transcriptomic dysregulation of keratinocytes. Interestingly, we found distinct populations of dendritic cells (DC) and memory T-cells that were largely absent in healthy control skin to persist in AD up to one year of treatment. These included LAMP3+ CCL22+ mature DC, CRTH2+ CD161+ Th2A cells, and CRTAM+ cytotoxic T-cells, expressing peak levels of CCL17 (DC) and IL13 (T-cells). Th2A cells showed a specific receptor constellation of IL17RB, IL1RL1 (ST2) and CRLF2, possibly rendering them key responders to the AD-typical epidermal alarmins IL25, IL33 and TSLP. We thus identified persisting mature DC and T-cells that maintained an inflammatory phenotype up to one year of treatment,equipped with all receptors to facilitate a keratinocyte-DC-Th2-mediated inflammatory response. These cell populations emerge as central players of a skin-intrinsic disease memory that leads to disease recurrences, and might therefore be promising targets to achieve a more sustained therapeutic response.

Testing the Reliability of Optical Coherence Tomography to Measure Epidermal Thickness and Distinguish Volar and Nonvolar Skin

“…Human skin can exhibit various phenotypes in different body sites, which can enable a difference in stress response and skin condition. The intrinsic properties of and relationship between the epidermis and dermis result in different skin phenotypes ( Chang et al, 2002 ; Garza et al, 2021 ; Sorrell et al, 2004 ) . Different phenotypes exhibit different properties.…”