title: Amelioration of human allograft arterial injury by atorvastatin or simvastatin correlates with reduction of interferon-gamma production by infiltrating T cells.
abstract: BACKGROUND
  Graft arteriosclerosis (GA) is an important factor limiting long-term outcomes after organ transplantation. We have used a chimeric humanized mouse system to model this arteriopathy in human vessels, and found that the morphologic and functional changes of experimental GA are interferon (IFN)-gamma dependent. This study evaluated whether 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, described as inhibitors of IFN-gamma production, affect GA in our model.
  
  
  METHODS
  C.B.-17 severe combined immunodeficiency-beige mice were transplanted with human artery segments as aortic interposition grafts and inoculated with allogeneic human peripheral blood mononuclear cells (PBMCs) or replication-deficient adenovirus encoding human IFN-gamma. Transplant arteries were analyzed from recipients treated with vehicle vs. atorvastatin or simvastatin at different doses. The effects of statins on T-cell alloresponses to vascular endothelial cells were also investigated in vitro.
  
  
  RESULTS
  Graft arteriosclerosis-like arteriopathy induced by PBMCs was reduced by atorvastatin at 30 mg/kg/day or simvastatin at 100 mg/kg/day that correlated with decreased graft-infiltrating CD3+ T cells. Circulating IFN-gamma was also reduced, as were graft IFN-gamma and IFN-gamma-inducible chemokine transcripts and graft human leukocyte antigen-DR expression. Graft arteriosclerosis directly induced by human IFN-gamma in the absence of human PBMCs was also reduced by atorvastatin, but only at the highest dose of 100 mg/kg/day. Finally, atorvastatin decreased the clonal expansion and production of interleukin-2, but not IFN-gamma, by human CD4+ T cells in response to allogeneic endothelial cells in coculture.
  
  
  CONCLUSIONS
  Our results suggest that a benefit of statin administration in transplantation may include amelioration of GA primarily by inhibiting alloreactive T-cell accumulation and consequent IFN-gamma production and secondarily through suppression of the arterial response to IFN-gamma.
authors.affiliation: Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Rao
authors.forename: Paul C Y
authors.initials: PC
authors.lastname: Tang
authors.forename: Yinong
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cuchara
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Colangelo
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: Marc I
authors.initials: MI
authors.lastname: Lorber
mesh_terms: D000328:Adult; D000818:Animals; D001158:Arteries / Q000637:transplantation; D000069059:Atorvastatin; D005434:Flow Cytometry; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D017710:Lymphocyte Transfusion; D051379:Mice; D016513:Mice, SCID; D011758:Pyrroles / Q000627:therapeutic use*; D019821:Simvastatin / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D007371:Interferon-gamma; D000069059:Atorvastatin; D019821:Simvastatin
references.citation: Circulation. 2003 Oct 28;108(17):2113-20
references.pmid: 14517172
references.citation: Nature. 2000 Jan 13;403(6766):207-11
references.pmid: 10646607
references.citation: Semin Vasc Med. 2004 Nov;4(4):401-6
references.pmid: 15861321
references.citation: J Immunol. 2007 Jan 1;178(1):592-604
references.pmid: 17182600
references.citation: Transplantation. 2003 Sep 27;76(6):891-9
references.pmid: 14508350
references.citation: Circ Res. 2007 Sep 14;101(6):560-9
references.pmid: 17656678
references.citation: Am J Transplant. 2004 Jul;4(7):1013-8
references.pmid: 15196056
references.citation: Transplantation. 1999 Mar 27;67(6):897-903
references.pmid: 10199740
references.citation: Am J Pathol. 1998 Aug;153(2):627-38
references.pmid: 9708821
references.citation: J Immunol. 2005 Oct 15;175(8):4886-96
references.pmid: 16210590
references.citation: J Exp Med. 2006 Feb 20;203(2):401-12
references.pmid: 16476765
references.citation: Nature. 2002 Nov 7;420(6911):78-84
references.pmid: 12422218
references.citation: Transplantation. 2005 Aug 15;80(3):332-8
references.pmid: 16082328
references.citation: Transplantation. 2006 Feb 27;81(4):559-66
references.pmid: 16495804
references.citation: FASEB J. 2004 Mar;18(3):606-8
references.pmid: 14734640
references.citation: Springer Semin Immunopathol. 2003 Sep;25(2):167-80
references.pmid: 12955465
references.citation: N Engl J Med. 2003 Aug 28;349(9):847-58
references.pmid: 12944570
references.citation: Semin Vasc Med. 2004 Nov;4(4):333-46
references.pmid: 15861315
references.citation: Semin Vasc Med. 2004 Nov;4(4):417-22
references.pmid: 15861323
references.citation: Immunity. 2001 Apr;14(4):387-97
references.pmid: 11336684
references.citation: Nephrol Dial Transplant. 2001 Sep;16(9):1738-41
references.pmid: 11522848
references.citation: Nephrol Dial Transplant. 2003 May;18(5):967-76
references.pmid: 12686673
references.citation: Circ Res. 2007 Mar 16;100(5):622-32
references.pmid: 17363708
references.citation: Semin Vasc Med. 2004 Nov;4(4):347-56
references.pmid: 15861311
references.citation: J Clin Invest. 2004 Sep;114(6):846-56
references.pmid: 15372109