LB1777 A novel ex vivo model of human hair follicle immune privilege collapse reveals the potential of farudodstat, a DHODH inhibitor, as a therapeutic for alopecia areata treatment

Alopecia areata (AA) is an inflammatory disorder of the hair follicles (HF) characterized by increased IFNγ levels, immune privilege (IP) collapse, and a Th1-mediated inflammatory response towards the hair bulb leading to premature catagen development, HF dystrophy and hair loss. Dihydroorotate dehydrogenase (DHODH) plays a key role in T-cell proliferation and its inhibition decreases Th1-cell differentiation and IFNγ production. In this study, we investigated whether farudodstat, a DHODH inhibitor, could be beneficial for the treatment of AA by means of an innovative model in which healthy human microdissected HFs were stimulated with anti-CD3/CD28 antibodies to promote intra- and peri-follicular T-cell activation via the T-cell receptor (TCR). The experimentally induced TCR stimulation ex vivo resulted in increased numbers of proliferative T-cell indicated by positive CD3+ and CD3+Ki-67+ cells in the HF epithelium and mesenchyme. Importantly, the expression of MHC I and II was significantly increased in the bulb epithelium and mesenchyme of anagen HFs stimulated with anti-CD3/CD28 antibodies, indicating loss of IP following T-cell activation. Treatment with 140 nM farudodstat significantly reduced the proliferation of T-cells, abrogated MHC protein expression, and also reduced the number of MHC II+ cells in the hair bulb. Of note, farudodstat treatment alone did not promote catagen induction and did not affect hair matrix keratinocyte proliferation or IP markers, suggesting no signs of cytotoxicity in healthy microdissected HFs. Our preliminary results show that T-cell activation via anti-CD3/CD28 treatment in the ex vivo model can successfully induce key features of AA including IP collapse. Additionally, our data suggest that the DHODH inhibitor farudodstatmay protect from IP collapse and offer a novel therapy for AA.