title: Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model.
abstract: Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation.
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Higginbotham
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Mathews
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Breeden
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Mingqing
authors.initials: M
authors.lastname: Song
authors.affiliation: Anatomic Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Alton Brad
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.affiliation: Department of Surgery, Indiana University Health Transplant Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lutz
authors.affiliation: Indiana University Health Transplant Department, Indianapolis, IN, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tector
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Newell
authors.affiliation: Department of Surgery, Indiana University Health Transplant Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: A Joseph
authors.initials: AJ
authors.lastname: Tector
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D064593:Heterografts / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000276:immunology; D016030:Kidney Transplantation / Q000379:methods; D008253:Macaca mulatta; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D007166:Immunosuppressive Agents; D023201:CD40 Ligand
keywords: costimulation blockade; human decay-accelerating factor; non-human primate; renal transplantation; transgenic pigs; xenoantigen; xenotransplantation; α-1,3-galactosyltransferase
references.citation: Transplantation. 2011 Feb 15;91(3):287-92
references.pmid: 21119562
references.citation: Am J Transplant. 2014 Aug;14(8):1895-900
references.pmid: 24909344
references.citation: Am J Transplant. 2010 Mar;10(3):535-46
references.pmid: 20415897
references.citation: Nat Med. 2006 Mar;12(3):304-6
references.pmid: 16501570
references.citation: Br Med Bull. 2006 May 24;75-76:99-114
references.pmid: 16723634
references.citation: Xenotransplantation. 2014 Sep-Oct;21(5):397-419
references.pmid: 25176336
references.citation: J Am Soc Nephrol. 2005 Sep;16(9):2732-45
references.pmid: 16049072
references.citation: Transplantation. 2014 Aug 27;98(4):419-26
references.pmid: 25243512
references.citation: Am J Transplant. 2011 May;11(5):947-57
references.pmid: 21521467
references.citation: Xenotransplantation. 2014 Nov-Dec;21(6):543-54
references.pmid: 25176027
references.citation: Transplantation. 2014 Aug 27;98(4):411-8
references.pmid: 25243511
references.citation: Am J Transplant. 2012 Mar;12(3):763-71
references.pmid: 22070772
references.citation: Am J Transplant. 2005 Mar;5(3):443-53
references.pmid: 15707398
references.citation: Kidney Int. 2001 Oct;60(4):1592-7
references.pmid: 11576378
references.citation: Cold Spring Harb Perspect Med. 2014 Apr 01;4(4):a015578
references.pmid: 24616201
references.citation: Diabetes. 2002 Feb;51(2):265-70
references.pmid: 11812731
references.citation: Transplant Proc. 2011 Nov;43(9):3426-30
references.pmid: 22099813
references.citation: J Am Soc Nephrol. 2012 Feb;23(2):225-35
references.pmid: 22114174
references.citation: Immunol Rev. 2014 Mar;258(1):241-58
references.pmid: 24517437
references.citation: Transplantation. 2000 Nov 15;70(9):1273-4
references.pmid: 11087140
references.citation: Am J Transplant. 2015 Jan;15(1):88-100
references.pmid: 25488654
references.citation: Xenotransplantation. 2008 Jul-Aug;15(4):268-76
references.pmid: 18957049
references.citation: Kidney Int. 2014 Feb;85(2):265-75
references.pmid: 24088952
references.citation: J Immunol. 2005 Jan 1;174(1):542-50
references.pmid: 15611281
references.citation: Xenotransplantation. 2015 Jan-Feb;22(1):20-31
references.pmid: 25178170
references.citation: Nat Med. 2005 Jan;11(1):29-31
references.pmid: 15619628
references.citation: Xenotransplantation. 2013 Jan-Feb;20(1):27-35
references.pmid: 23384142
references.citation: J Thorac Cardiovasc Surg. 2014 Sep;148(3):1106-13; discussion 1113-4
references.pmid: 24998698
references.citation: Xenotransplantation. 2012 Mar-Apr;19(2):92-101
references.pmid: 22497511
references.citation: J Exp Med. 2014 Feb 10;211(2):297-311
references.pmid: 24493803
references.citation: Nat Rev Nephrol. 2014 Jan;10(1):14-24
references.pmid: 24100403
references.citation: Transplantation. 2007 Jul 27;84(2):244-50
references.pmid: 17667817
references.citation: Transplantation. 2000 Nov 15;70(9):1323-31
references.pmid: 11087147
references.citation: Transplantation. 2000 Jul 15;70(1):15-21
references.pmid: 10919569
references.citation: Am J Transplant. 2013 Nov;13(11):3021-30
references.pmid: 24007441
references.citation: Transplantation. 2008 Jan 15;85(1):118-24
references.pmid: 18192921
references.citation: Transplantation. 2007 Jan 27;83(2):193-201
references.pmid: 17264816
references.citation: Nat Med. 2005 Dec;11(12):1295-8
references.pmid: 16311604
references.citation: Transplantation. 2014 Aug 15;98 (3):267-76
references.pmid: 24992357
references.citation: Sci Transl Med. 2010 Feb 3;2(17):17ra10
references.pmid: 20371478
references.citation: Am J Transplant. 2015 Feb;15(2):358-70
references.pmid: 25612490