Alopecia areata (AA) is an immune-mediated hair follicle (HF) disorder induced by elevated IFNγ levels and a Tc1-driven inflammatory response. We have previously shown that treatment with IL-12 and IL-18 induces IFNγ-dependent, immune privilege collapse of the hair bulb, which can be inhibited by blocking IL-12 receptor signaling with the TYK2 inhibitor, BMS-986202 (BMS), in human microdissected HFs. Here, we further investigate the role of TYK2 and its inhibition in AA pathogenesis. We cultured human full thickness non-lesional and lesional scalp skin biopsies from acute or chronic AA patients ex vivo with BMS. In addition, oral treatment with BMS or tofacitinib was performed in the well-established humanized mouse model for AA. Samples were then processed for quantitative (immuno-)histomorphometry. BMS treatment prolonged anagen in non-lesional and lesional HFs of acute AA scalp biopsies, and reduced expression of MHC I and number of MHC II+ cells in the bulb of acute lesional samples. Moreover, it diminished the number of intra- and peri-follicular CD3+ T cells in unstimulated acute, and unstimulated/stimulated chronic, lesional AA scalp biopsies. IFNg release was decreased in the presence of BMS in the culture medium of stimulated acute and chronic lesional biopsies. In the humanized mouse model, treatment with BMS or tofacitinib significantly increased hair shaft numbers and microscopically detected anagen I-VI HFs, reduced HM keratinocyte apoptosis and HF dystrophy, decreased MHC class I and II expression, and diminished numbers of MHC class II+ cells and infiltrating CD3+ T cells. Taken together, our results suggest TYK2 inhibition is a novel, pharmacological strategy for AA management, deserving clinical exploration.
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