Selective blockade of γc pathway ameliorates alopecia areata in a humanized murine model

Alopecia areata (AA) is a chronic autoimmune disease characterized by sudden patchy hair loss and persistent inflammation. To date, only Jak inhibitors have been approved for AA treatment, but United States Food and Drug Administration-issued black box warnings highlight the need for alternative therapies. We previously reported that an anti-γc antibody, hC2, inhibits autoreactive B, T, and NK cells by selectively attenuating Jak/signal transducer and activator of transcription signaling induced by 6 γc cytokines without affecting off-target TEC kinase pathways. In this study, we sought to define the mechanism of action and efficacy of hC2 in AA using an ex vivo T-cell platform and a xenogeneic AA-like mouse model induced by human T-cell engraftment. Analyses showed that hC2 could restore hair follicle homeostasis and suppress hair loss by inhibiting autoreactive T-cell activity and the proliferation of tissue-resident memory T cells. Although the Jak3 inhibitor ritlecitinib could potentially protect hair follicles through a T-cell depletion strategy in vitro, severe side effects were associated with ritlecitinib treatment, whereas no significant safety issues were noted after hC2 treatment in the xenogeneic AA-like mouse model. These findings suggest that hC2 might offer a safer and more effective therapeutic approach for patients with AA in the future.