Engineered Tissue Tregs ameliorate inflammatory and ischemic diseases 3661

Abstract Description Regulatory T cells (Tregs) play a central role in establishing immune tolerance, with a subset of these cells, dubbed Tissue Tregs, orchestrating specialized function including tissue repair, making them an ideal candidate for intervention in life-threatening acute inflammatory and ischemic diseases. We report the generation of human Tissue Engineered Tregs (Tissue EngTregs) through a gene editing approach of PBMC isolated CD4+ T cells, leading to stable FOXP3 expression, a rapamycin-activated signaling complex that provides tunable IL-2 signal, and expression of an alarmin sensitive transgene. Tissue EngTregs express key tolerogenic markers (e.g. CD25, CTLA4), enhanced homing receptors (e.g. CCR5, CCR8) and soluble repair mediators. Adoptive transfer of surrogate CB6F1 allogeneic murine Engineered Tregs (mEngTregs) ameliorated disease in murine models of Acute Lung Injury (ALI), Acute Kidney Injury (AKI), and ischemic stroke. mEngTreg treated mice presented with significantly reduced inflammation (e.g. lower BAL neutrophil counts in ALI and lower Kim-1 in AKI models respectively), correlated with better outcomes by H&E, and ultimately resulted in improved tissue function (e.g. increased oxygen saturation for ALI and reduced Sr. BUN, Cr levels in the case of AKI). Overall, Tissue EngTregs harness both tolerogenic and reparative properties and represent an exciting therapeutic option for ischemic and inflammatory diseases. Funding Sources Private capitol including Novartis Venture Fund, OrbiMed, RA Capital. Topic Categories Translational and Interventional Immunology (TI)