title: In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells.
abstract: Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term. These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts. Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis. Therefore, we designed this study to test the hypothesis that human regulatory T cells (T(reg) cells) expanded ex vivo can prevent transplant arteriosclerosis. Here we show the comparative capacity of T(reg) cells, sorted via two separate strategies, to prevent transplant arteriosclerosis in a clinically relevant chimeric humanized mouse system. We found that the in vivo development of transplant arteriosclerosis in human arteries was prevented by treatment of ex vivo-expanded human T(reg) cells. Additionally, we show that T(reg) cells sorted on the basis of low expression of CD127 provide a more potent therapy to conventional T(reg) cells. Our results demonstrate that human T(reg) cells can inhibit transplant arteriosclerosis by impairing effector function and graft infiltration. We anticipate our findings to serve as a foundation for the clinical development of therapeutics targeting transplant arteriosclerosis in both allograft transplantation and other immune-mediated causes of vasculopathy.
authors.affiliation: Transplantation Research Immunology Group, Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Satish N
authors.initials: SN
authors.lastname: Nadig
authors.forename: Joanna
authors.initials: J
authors.lastname: Wieckiewicz
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wu
authors.forename: Gregor
authors.initials: G
authors.lastname: Warnecke
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Shiqiao
authors.initials: S
authors.lastname: Luo
authors.forename: Alexandru
authors.initials: A
authors.lastname: Schiopu
authors.forename: David P
authors.initials: DP
authors.lastname: Taggart
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D001161:Arteriosclerosis / Q000276:immunology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D006084:Graft Rejection; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008323:Mammary Arteries / Q000637:transplantation*; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D007371:Interferon-gamma
references.citation: Blood. 2005 Mar 1;105(5):2220-6
references.pmid: 15546950
references.citation: Diabetes. 2009 Mar;58(3):652-62
references.pmid: 19074986
references.citation: Kidney Int. 1998 Feb;53(2):465-72
references.pmid: 9461108
references.citation: Microsurgery. 1995;16(2):110-3
references.pmid: 7783601
references.citation: Blood. 2004 Aug 1;104(3):895-903
references.pmid: 15090447
references.citation: Circ Res. 2007 Sep 14;101(6):560-9
references.pmid: 17656678
references.citation: Transplantation. 2007 Jun 15;83(11):1459-65
references.pmid: 17565319
references.citation: J Immunol. 2005 Jun 15;174(12):7573-83
references.pmid: 15944257
references.citation: Circ Res. 2007 Mar 16;100(5):622-32
references.pmid: 17363708
references.citation: J Am Coll Cardiol. 2005 May 3;45(9):1532-7
references.pmid: 15862430
references.citation: J Heart Lung Transplant. 2006 Aug;25(8):869-79
references.pmid: 16890107
references.citation: Nature. 2000 Jan 13;403(6766):207-11
references.pmid: 10646607
references.citation: J Clin Invest. 2004 Sep;114(6):762-4
references.pmid: 15372099
references.citation: Nat Rev Immunol. 2003 Mar;3(3):199-210
references.pmid: 12658268
references.citation: J Exp Med. 2006 Jul 10;203(7):1693-700
references.pmid: 16818676
references.citation: Blood. 2004 Jul 15;104(2):453-61
references.pmid: 15031211
references.citation: J Immunol. 2007 Sep 15;179(6):3578-87
references.pmid: 17785792
references.citation: J Immunol. 2007 Oct 15;179(8):5246-54
references.pmid: 17911610
references.citation: N Engl J Med. 2003 Dec 11;349(24):2326-33
references.pmid: 14668458
references.citation: Am J Transplant. 2008 Feb;8(2):338-47
references.pmid: 18211507
references.citation: J Exp Med. 1992 Jun 1;175(6):1565-73
references.pmid: 1375266
references.citation: J Thorac Cardiovasc Surg. 2005 Feb;129(2):250-3
references.pmid: 15678032
references.citation: J Immunol. 1995 Aug 1;155(3):1151-64
references.pmid: 7636184
references.citation: J Exp Med. 2006 Jul 10;203(7):1701-11
references.pmid: 16818678
references.citation: Nat Immunol. 2002 Dec;3(12):1208-13
references.pmid: 12415266
references.citation: Expert Rev Mol Med. 2003 Jan 13;5(2):1-23
references.pmid: 14987399
references.citation: J Heart Transplant. 1990 Jul-Aug;9(4):339-45
references.pmid: 2398426