Off-the-shelf reparative treg to resolve tissue damage and inflammation after acute lung injury 4031

Abstract Description Damage releases IL-33 from the injured stroma to stimulate to cells expressing the IL-33 receptor, ST2. Regulatory T cells (Treg) can express ST2 and respond to IL-33 by proliferating and secreting repair-promoting molecules like IL-13 and amphiregulin. Published studies show the importance of IL-33 and Treg after acute lung injury (ALI). Thus, we hypothesized that adoptive cell therapy (ACT) with ex vivo generated “reparative” Tregs (RepTregs) will resolve damage after ALI to limit mortality and morbidity. To date, Treg ACT preclinical and clinical testing has primarily relied on expanded autologous cells that require lengthy manufacturing. This would thwart application of Treg early after ALI. To address this, we compared cryopreserved syngeneic (Syn; B6) versus allogeneic (Allo; BALB/c or F1) polyclonal “suppressive” Treg (SupTreg) that were expanded for 14 days with IL-2 and CD3/CD28 stimulation to RepTregs expanded with IL-2, IL-33, and CD3/CD28 stimulation as an “off-the-shelf” immunotherapy in pre-clinical mouse models (B6) of ALI. We demonstrate that both Syn and Allo RepTregs, but not SupTreg, reduced morbidity when thawed and delivered iv 24 hours post ALI. Syn and Allo Treg were present in the lung interstitium at day 7 post-delivery and protection was associate with an augmented presence of alveolar and CD301b+ monocyte-derived macrophages. RepTreg ACT is a clinically-implementable therapeutic intervention to avoid severe complications after ALI. Funding Sources Supported by T32 EB001026 (KJB); DoD Discovery Award PR230360 (HRT) Topic Categories Vaccines and Immunotherapy (VAC)