Allogeneic Tissue Tregs Improve Disease Outcome in Models of Acute Lung and Kidney Injury 2259889

Abstract

Abstract Introduction Foxp3+ T regulatory cells (Tregs) are important mediators of tissue homeostasis and immune tolerance, known for suppressive capabilities as well as noncanonical tissue repair functions. Acute inflammatory diseases such as acute lung injury (ALI) and acute kidney injury (AKI) are life-threatening conditions characterized by unchecked inflammation and maladaptive tissue repair. Methods We engineer Tregs for stable expression of Foxp3, a rapamycin-activated chemically inducible signaling complex that provides targeted IL-2 signaling, and expression of the tissue damage alarmin receptor ST2. Results Engineered cells (Tissue EngTregs) recapitulate the gene signature observed in naturally occurring Tissue Tregs based on bulk RNAseq analysis. We assessed the ability of a murine surrogate cell (mEngTreg) to achieve efficacy in mouse models of ALI and AKI. mEngTregs showed efficacy in all models based on key disease-specific biomarkers. In ALI, mEngTreg treatment was associated with restored blood oxygen saturation, reduced immune infiltrates by flow cytometry, lower levels of BAL inflammatory cytokines, and reduced tissue damage by H&E. In AKI, mEngTregs treatment led to lower levels of serum creatinine, Blood Urea Nitrogen, NGAL, and Kim-1 as well as reduced tubular degeneration, cast formation, and loss of brush border by H&E. Conclusion Overall, these data support the development of a potent off-the-shelf allogeneic engineered Treg therapy for human acute lung or kidney diseases. Funding Source NIH-SBIR, venture Topic Categories Vaccines and Immunotherapy (VAC)