JAK inhibitors (JAKi), a major advance in AA therapy may not restore hair follicle’s (HF) physiological immune privilege (IP). Yet, HF IP collapse is required for AA to develop, while HFs with intact/restored IP are relatively AA-resistant. Therefore, additional therapeutics are needed that target pathogenic pathways in AA that are unaffected by JAKi. Namely, NKG2D on T and NK cells is activated by the epithelial distress signal, MICA (e.g., by “stressed” HFs), leading to HF IP collapse-inducing IFNg secretion by T/NK cells. Statins may up-regulate expression/activity of the metalloproteinases, ADAM10 and 17, which enhance MICA shedding and may suppress pathogenic MICA-NKG2D interactions. To test this hypothesis in an AA context, we have co-cultured human outer root sheath keratinocytes (ORS-KCs) with human Vd1+T Cells (TCs). These transitional immunity TCs are increased in both lesional and non-lesional AA skin, secrete IFNg via the above MICA-NKG2D mechanism, and attack “stressed” HFs in an AA-like manner ex vivo. ORS-KCs were pre-treated with vehicle, IFNg or H2O2 to imitate HF IP collapse conditions and oxidative damage-induced HF stress. After 24h, an equal number of human dermal Vd1+TCs was added for 48h, followed by FACS analysis. This showed that Vd1+TCs become activated (increased CD69+/NKG2D+ expression) and up-regulate cytotoxic proteins (perforin, granzyme B) when co-cultured with INFg or H2O2-treated ORS-KC. Moreover, MICA expression by ORS-KCs is up-regulated after oxidative stress, which can be counteracted by lovastatin treatment in vitro. Lovastatin also up-regulates both ADAM10 and 17 on ORS-KCs, which should enhance MICA shedding. This pilot study supports to systematically re-examine well-tolerated statins as a potential adjunct AA therapeutic in future AA management that down-regulates pathogenic, “innate” NKG2D-MICA interactions.

ESDR026 - Targeting pathogenic MICA-NKG2D interactions by statins: A novel adjunct treatment strategy for alopecia areata management?

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.