366 Blocking the IL-22 receptor represents a novel treatment option for atopic eczema

Abstract

Atopic eczema (AE) is a chronic inflammatory skin disease that presents with elevated levels of type 2 cytokines but also elevated IL-22 expression in lesional skin. The objective of this study is to evaluate a novel IL-22 receptor blocking antibody for AE and demonstrate a difference in mechanism of action to IL-4RA inhibition. Expression of IL-22RA was identified in healthy and AE skin samples by in situ hybridization (ISH). In vitro, primary human keratinocytes were cultured in an air liquid interface (3D) and stimulated with supernatant derived from activated AE lesional T cells (SN) in presence or absence of an IL-22RA1 or an IL-4RA blocking antibody as comparator. Furthermore, fresh AE biopsies were cultured ex vivo in presence or absence of these blocking antibodies. All models were analyzed by real time PCR, RNA sequencing and histology. ISH of IL-22RA1 mRNA revealed only sporadic expression in stratum granulosum predominantly of healthy skin. In contrast, in AE skin IL-22RA1 expression was denser and sporadically expressed in the stratum spinosum and stratum basale. Histological evaluation of 3D human skin models revealed that blocking IL-22RA1 led to a reduction of IL-22 induced acanthosis. On gene expression level, IL-22RA1 inhibition of AE T cell SN stimulated models, significantly reduced expression of DEFB4 but had no effect on CCL2 levels. In contrary, IL-4RA inhibition significantly reduced CCL2 expression, whereas DEFB4 was increased. RNA sequencing of 3D models and in vitro stimulated AE skin revealed different mode of actions of IL-22RA1 and IL-4RA inhibition highlighting the distinct pathways both cytokines use to contribute to disease pathology. In conclusion, IL-22R inhibition shows a different mode of action compared to IL-4RA blocking and could be a powerful alternative therapeutic option to Dupilumab to treat AE.