title: Targeting Sirtuin-1 prolongs murine renal allograft survival and function.
abstract: Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3(+) T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3(+) T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1(fl/fl)CD4(cre)) or mice treated with a Sirtuin-1-specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1(fl/fl)CD4(cre) recipients showed markedly longer survival and improved kidney function. Sirt1(fl/fl)CD4(cre) recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell-mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration.
authors.affiliation: Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Levine
authors.affiliation: Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia and University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia and University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tricia R
authors.initials: TR
authors.lastname: Bhatti
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia and University of Pennsylvania, Philadelphia, PA, USA. Electronic address: beieru@email.chop.edu.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Beier
mesh_terms: D064591:Allografts; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D005260:Female; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: acute rejection; chronic allograft nephropathy; tolerance