Expression of human CD47 in pig glomeruli prevents proteinuria and prolongs graft survival following pig-to-baboon xenotransplantation.
CD47
kidney
podocyte
preclinical model
proteinuria
xenotransplantation
Journal
Xenotransplantation
ISSN: 1399-3089
Titre abrégé: Xenotransplantation
Pays: Denmark
ID NLM: 9438793
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
29
07
2021
received:
28
04
2021
accepted:
01
08
2021
pubmed:
22
8
2021
medline:
28
1
2022
entrez:
21
8
2021
Statut:
ppublish
Résumé
Nephrotic syndrome is a common complication of pig-to-baboon kidney xenotransplantation (KXTx) that adversely affects outcomes. We have reported that upregulation of CD80 and down-regulation of SMPDL-3b in glomeruli have an important role in the development of proteinuria following pig-to-baboon KXTx. Recently we found induced expression of human CD47 (hCD47) on endothelial cells and podocytes isolated from hCD47 transgenic (Tg) swine markedly reduced phagocytosis by baboon and human macrophages. These observations led us to hypothesize that transplanting hCD47 Tg porcine kidneys could overcome the incompatibility of the porcine CD47-baboon SIRPα interspecies ligand-receptor interaction and prevent the development of proteinuria following KXTx. Ten baboons received pig kidneys with vascularized thymic grafts (n = 8) or intra-bone bone marrow transplants (n = 2). Baboons were divided into three groups (A, B, and C) based on the transgenic expression of hCD47 in GalT-KO pigs. Baboons in Group A received kidney grafts with expression of hCD47 restricted to glomerular cells (n = 2). Baboons in Group B received kidney grafts with high expression of hCD47 on both glomerular and tubular cells of the kidneys (n = 4). Baboons in Group C received kidney grafts with low/no glomerular expression of hCD47, and high expression of hCD47 on renal tubular cells (n = 4). Consistent with this hypothesis, GalT-KO/hCD47 kidney grafts with high expression of hCD47 on glomerular cells developed minimal proteinuria. However, high hCD47 expression in all renal cells including renal tubular cells induced an apparent destructive inflammatory response associated with upregulated thrombospondin-1. This response could be avoided by a short course of weekly anti-IL6R antibody administration, resulting in prolonged survival without proteinuria (mean 170.5 days from 47.8 days). Data showed that transgenic expression of hCD47 on glomerular cells in the GalT-KO donor kidneys can prevent xenograft nephropathy, a significant barrier for therapeutic applications of xenotransplantation. The ability to prevent nephrotic syndrome following KXTx overcomes a critical barrier for future clinical applications of KXTx.
Sections du résumé
BACKGROUND
Nephrotic syndrome is a common complication of pig-to-baboon kidney xenotransplantation (KXTx) that adversely affects outcomes. We have reported that upregulation of CD80 and down-regulation of SMPDL-3b in glomeruli have an important role in the development of proteinuria following pig-to-baboon KXTx. Recently we found induced expression of human CD47 (hCD47) on endothelial cells and podocytes isolated from hCD47 transgenic (Tg) swine markedly reduced phagocytosis by baboon and human macrophages. These observations led us to hypothesize that transplanting hCD47 Tg porcine kidneys could overcome the incompatibility of the porcine CD47-baboon SIRPα interspecies ligand-receptor interaction and prevent the development of proteinuria following KXTx.
METHODS
Ten baboons received pig kidneys with vascularized thymic grafts (n = 8) or intra-bone bone marrow transplants (n = 2). Baboons were divided into three groups (A, B, and C) based on the transgenic expression of hCD47 in GalT-KO pigs. Baboons in Group A received kidney grafts with expression of hCD47 restricted to glomerular cells (n = 2). Baboons in Group B received kidney grafts with high expression of hCD47 on both glomerular and tubular cells of the kidneys (n = 4). Baboons in Group C received kidney grafts with low/no glomerular expression of hCD47, and high expression of hCD47 on renal tubular cells (n = 4).
RESULTS
Consistent with this hypothesis, GalT-KO/hCD47 kidney grafts with high expression of hCD47 on glomerular cells developed minimal proteinuria. However, high hCD47 expression in all renal cells including renal tubular cells induced an apparent destructive inflammatory response associated with upregulated thrombospondin-1. This response could be avoided by a short course of weekly anti-IL6R antibody administration, resulting in prolonged survival without proteinuria (mean 170.5 days from 47.8 days).
CONCLUSION
Data showed that transgenic expression of hCD47 on glomerular cells in the GalT-KO donor kidneys can prevent xenograft nephropathy, a significant barrier for therapeutic applications of xenotransplantation. The ability to prevent nephrotic syndrome following KXTx overcomes a critical barrier for future clinical applications of KXTx.
Identifiants
pubmed: 34418164
doi: 10.1111/xen.12708
pmc: PMC8957703
mid: NIHMS1785087
doi:
Substances chimiques
CD47 Antigen
0
CD47 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12708Subventions
Organisme : NIAID NIH HHS
ID : P01 AI045897
Pays : United States
Organisme : NIH HHS
ID : S10 OD020056
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027050
Pays : United States
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
J Immunol Methods. 1991 Jun 3;139(2):271-9
pubmed: 1710634
Am J Transplant. 2015 Feb;15(2):358-70
pubmed: 25612490
Transplantation. 2006 Jan 15;81(1):26-35
pubmed: 16421473
Am J Transplant. 2014 Dec;14(12):2713-22
pubmed: 25278264
Transplantation. 2006 Aug 15;82(3):314-9
pubmed: 16906027
Am J Transplant. 2018 Apr;18(4):855-867
pubmed: 29087049
Am J Surg. 2010 Nov;200(5):615-9
pubmed: 21056139
Transplantation. 2002 Mar 15;73(5):826-31
pubmed: 11907438
Nat Med. 2005 Jan;11(1):32-4
pubmed: 15619627
Nat Med. 1996 Nov;2(11):1211-6
pubmed: 8898747
Xenotransplantation. 2020 Jan;27(1):e12549
pubmed: 31495971
Transplantation. 1999 Dec 15;68(11):1684-92
pubmed: 10609944
Xenotransplantation. 2018 Sep;25(5):e12391
pubmed: 29527745
Transplantation. 2009 Oct 27;88(8):1019-24
pubmed: 19855248
Kidney Int. 2012 Jun;81(12):1226-38
pubmed: 22418977
Transplantation. 2003 May 27;75(10):1615-24
pubmed: 12777846
J Allergy Clin Immunol. 2013 Aug;132(2):426-36.e8
pubmed: 23562609
JCI Insight. 2019 Mar 19;5:
pubmed: 30888336
Am J Transplant. 2009 Dec;9(12):2669-78
pubmed: 19845583
Transpl Int. 2018 Oct;31(10):1164-1177
pubmed: 29722117
Xenotransplantation. 2019 Jul;26(4):e12516
pubmed: 30989742
J Immunol. 2000 Mar 15;164(6):3079-86
pubmed: 10706697
Xenotransplantation. 2019 Mar;26(2):e12459
pubmed: 30136356
Cell Oncol (Dordr). 2020 Feb;43(1):19-30
pubmed: 31485984
Pediatr Nephrol. 2020 Oct;35(10):1887-1896
pubmed: 32399663
Transpl Int. 1992;5 Suppl 1:S116-20
pubmed: 14621752
J Am Soc Nephrol. 2014 Apr;25(4):737-44
pubmed: 24459229
Bone Marrow Transplant. 2013 Mar;48(3):452-8
pubmed: 23208313
Transplantation. 2005 Dec 27;80(12):1783-90
pubmed: 16378075
Methods Mol Biol. 2020;2110:151-171
pubmed: 32002908
Pediatr Nephrol. 2013 Sep;28(9):1803-12
pubmed: 23689904
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3827-32
pubmed: 15007168
Am J Transplant. 2015 Apr;15(4):974-83
pubmed: 25676635
J Immunobiol. 2017 Jun;2(2):
pubmed: 28725880
Am J Transplant. 2017 Jul;17(7):1778-1790
pubmed: 28117931
Transplantation. 2014 Aug 27;98(4):411-8
pubmed: 25243511
Nephrol Dial Transplant. 2012 Jan;27(1):81-9
pubmed: 21617192
Xenotransplantation. 2020 Jan;27(1):e12552
pubmed: 31544995
J Immunol. 1995 Dec 1;155(11):5249-56
pubmed: 7594537
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5062-6
pubmed: 17360380
Nature. 2018 Dec;564(7736):430-433
pubmed: 30518863
J Clin Invest. 2005 Dec;115(12):3451-9
pubmed: 16294224
J Immunol. 2014 Apr 1;192(7):3442-50
pubmed: 24591363
Matrix Biol. 2014 Jul;37:92-101
pubmed: 24418252
Cardiovasc Pathol. 2015 Jul-Aug;24(4):199-206
pubmed: 25958013