Treg-targeted therapies restrain disease in a murine model of alopecia areata

Summary: Abstract Body: Alopecia Areata (AA) is a common autoimmune disease that presents as nonscarring hair loss. Current FDA-approved treatments for AA are limited to JAK inhibitors; however, potential adverse effects and refractory patients invites the development of alternative therapeutic strategies. Our lab has shown that selective depletion of regulatory T cells (Tregs) in the C3H/HeJ murine model of AA enhances disease development, suggesting that Tregs may play a role in defending the hair follicle from attack. We have also observed that emergence of disease is marked by a robust expansion of CD8 effector T cells (Teffs) that results in this population outnumbering Tregs 20-fold. We hypothesized that pharmacologic enhancement of the Treg pool may be an effective strategy for modulating disease. While low dose recombinant human IL-2 (hIL-2) for the purpose of Treg expansion has not shown great promise for AA patients, IL-2 fusion proteins have shown benefits in other disease models and offer advantages over hIL-2. HCW9302 is a recombinant fusion protein containing two human IL-2 domains fused to a soluble human tissue factor domain. It has a longer half-life than hIL-2 and can selectively expand and activate either human or murine Tregs. Using a murine skin-graft induction model of AA, we observed HCW9302 treatment protected mice from developing AA. We also noted a significant reduction in the number of Teff found infiltrating the skin and a recovery of skin Tregs to outnumber Teff 4:1. Overall, our findings suggest that Tregs play a protective role towards the hair follicle, and their enhancement is effective at restraining disease. Our data provides translational support for the use of IL-2 fusion proteins as a therapeutic strategy for patients with AA. Maddison Lensing^{1, 2}, Samuel J. Connell^{1, 2}, Peter Rhode⁴, Niraj Shrestha⁴, Xiayoun Zhu⁴, Hing C. Wong⁴, Ali Jabbari^{1, 2, 3} 1. Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, United States. 2. Department of Dermatology, University of Iowa Health Care, Iowa City, IA, United States. 3. Iowa City VA Medical Center, Iowa City, IA, United States. 4. HCW Biologics, Miramar, FL, United States. Adaptive and Auto-Immunity