IL-15 as a Candidate Key Cytokine in Alopecia Areata Pathobiology
The purpose of this project is to test the hypothesis that blockade of interleukin-15 (IL-15) or IL-15 receptor-alpha can provide therapeutic benefit in alopecia areata.
Effective alopecia areata (AA) treatment requires selective targeting of the key pathomechanisms to combine optimal, long-lasting therapy outcomes with reduced adverse effects. Recent research has suggested that the multi-function cytokine, interleukin-15 (IL-15), is important in AA pathobiology. Yet, convincing evidence for this remains to be generated in the human system. Specifically, since collapse of the hair follicle’s (HF) physiological immune privilege (IP) is an essential prerequisite for AA lesions to develop while HF-IP restoration is required for hair regrowth, it is critical to clarify the impact of IL-15 on human HF-IP - either directly, or indirectly. Here, we propose to do this by asking (in optimally suited, perfectly complementary human ex vivo and in vivo assay systems, i.e. AA patient skin biopsies, scalp HF organ culture and the humanized AA mouse model) whether: a) IL-15 and/or IL-15 receptor-alpha expression in/around lesional and non-lesional AA HFs is abnormal compared to healthy human scalp skin; b) IL-15 alone induces and/or enhances IFNγ-induced human HF-IP collapse; c) selectively antagonizing IL-15 receptor-alpha mediated signaling prevents experimentally induced HF-IP collapse and/or even restores HF-IP and promotes human hair regrowth in vivo; d) IL-15 promotes IFNγ secretion by pathogenic T/NK cells and/or promotes pathological perifollicular mast cell/T cell interactions in vivo. These clinically highly relevant studies will clarify whether IL-15 signaling really deserves selective targeting in future AA management, which adverse HF effects this could exert, and whether there is subgroup of AA patients who likely will benefit most from this.
If successful, this study could provide new insights into the mechanism of alopecia areata pathogenesis mediated by IL-15 with important implications for future therapeutic intervention.