055 IL-15 contributes to atopic dermatitis pathogenesis: Lessons from a novel humanized mouse disease model

Atopic dermatitis (AD) lesions are characterized by high expression of interleukin-15 (IL-15), a pleiotropic cytokine that controls NK and T-cell activation keratinocyte apoptosis, although the role IL-15 signaling in AD pathobiology remains unclear. Here, we have explored this novel humanized mouse model, which is based on intradermal injection autologous,in vitro pre-stimulated with IL-4/IL-2/LPS PBMCs into healthy human skin xenotransplants from non-atopic donors grafted onto SCID/beige mice. Monoclonal antibodies against (CALY-002), or IL-4Rα (Dupilumab, DUPI), IgG were administered to these mice i.v. either prophylactically therapeutically. dominant Th2 pattern facilitated Th1/17/22 cytokines developed within two weeks. Quantitative (immuno-)histomorphometry experimentally-induced confirmed up-regulation epidermal IL-15RA protein expression, as well an increased number IL-15+ IL-15RA+ cells papillary dermis. Just like DUPI, inhibition CALY-002 ameliorated clinical disease signs improved barrier integrity, i.e. significantly Filaggrin reduced thickness, hyperproliferation. also prevented/rescued IL-15+, IL-17+, IL-22+ IFNg+cells xenotransplants, yet did not affect CD3+ numbers (unlike DUPI). Nanostring-based transcriptomics revealed downregulates AD-relevant genes including alarmins, defensins, receptors Th1 transcription factors, may promote exhaustion regulate B-cell activity. Thus, functionally contributes pathogenesis, deserves further exploration therapeutic target reduce inflammation AD.