Targeting sirtuin-1 improves murine renal allograft survival and function (TRAN3P.901)

Pharmacologic inhibition of sirtuin-1 (Sirt1) augments suppressive functions of Foxp3+ regulatory T cells (Treg) and prolongs murine cardiac allograft survival. We investigated if Sirt1 targeting produced longer allograft function and allograft-dependent survival in a MHC-mismatched renal transplant model. After transplantation of BALB/c kindey allografts into C57Bl/6 wild type or fl-Sirt1/CD4cre recipients, native kidneys were removed three days post-operatively. We followed the mice for survival, and allograft function by weekly serum electrolyte and renal function (BUN, creatinine), as well as hematocrit. We observed, that loss of Sirt1 in T cells led to prolonged median renal allograft-dependent survival from 14 days (IQR: 11-91.25) to 143 days (IQR: 27-147) in wild type controls vs. fl-Sirt1/CD4cre recipients (Mantel-Cox, p 100 days) became tolerant to antigen re-challenge with a BALB/c, but rejected third-party C3H cardiac allografts. In conclusion, deletion of Sirt1 in T cells is effective at prolonging allograft function and allograft-dependent survival.