Mixed xenogeneic porcine chimerism tolerizes human anti-pig natural antibody-producing cells in a humanized mouse model.
B cells
Mixed Chimerism
humanized mice
xenoantibody
xenotolerance
Journal
Xenotransplantation
ISSN: 1399-3089
Titre abrégé: Xenotransplantation
Pays: Denmark
ID NLM: 9438793
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
11
03
2021
received:
15
01
2021
accepted:
09
04
2021
pubmed:
28
4
2021
medline:
18
9
2021
entrez:
27
4
2021
Statut:
ppublish
Résumé
A major obstacle to the success of organ transplantation from pigs to humans, necessitated by the shortage of human organs, is robust humoral immune rejection by pig-reactive human antibodies. Mixed xenogeneic hematopoietic chimerism induces xenoreactive B cell tolerance in rodents, but whether mixed pig/human chimerism could induce tolerance of human B cells to pig xenoantigens is unknown. We investigated this question using a humanized mouse model in which durable mixed (pig-human) xenogeneic chimerism can be established. Human natural anti-pig cytotoxic antibodies, predominantly IgM, are detectable in non-chimeric humanized mouse serum, and pig-reactive antibodies were reduced in mixed chimeric versus non-chimeric humanized mice. This difference required persistent mixed chimerism and was not due to the adsorption of antibodies on pig cells in vivo. Furthermore, human B cells from spleens of mixed chimeric mice produced lower levels of anti-pig antibodies when stimulated in vitro compared with those from non-chimeric mice. Our findings demonstrate that mixed chimerism reduces human natural antibodies to pig xenoantigens, providing the first in vivo evidence of human B cell tolerance induction by mixed xenogeneic chimerism and supporting further evaluation of this approach for inducing human B cell tolerance to xenografts.
Sections du résumé
BACKGROUND
A major obstacle to the success of organ transplantation from pigs to humans, necessitated by the shortage of human organs, is robust humoral immune rejection by pig-reactive human antibodies. Mixed xenogeneic hematopoietic chimerism induces xenoreactive B cell tolerance in rodents, but whether mixed pig/human chimerism could induce tolerance of human B cells to pig xenoantigens is unknown.
METHODS
We investigated this question using a humanized mouse model in which durable mixed (pig-human) xenogeneic chimerism can be established.
RESULTS
Human natural anti-pig cytotoxic antibodies, predominantly IgM, are detectable in non-chimeric humanized mouse serum, and pig-reactive antibodies were reduced in mixed chimeric versus non-chimeric humanized mice. This difference required persistent mixed chimerism and was not due to the adsorption of antibodies on pig cells in vivo. Furthermore, human B cells from spleens of mixed chimeric mice produced lower levels of anti-pig antibodies when stimulated in vitro compared with those from non-chimeric mice.
CONCLUSIONS
Our findings demonstrate that mixed chimerism reduces human natural antibodies to pig xenoantigens, providing the first in vivo evidence of human B cell tolerance induction by mixed xenogeneic chimerism and supporting further evaluation of this approach for inducing human B cell tolerance to xenografts.
Identifiants
pubmed: 33904221
doi: 10.1111/xen.12691
pmc: PMC8376778
mid: NIHMS1707585
doi:
Substances chimiques
Antigens, Heterophile
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12691Subventions
Organisme : NIAID NIH HHS
ID : R01 AI084903
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027050
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI045897
Pays : United States
Organisme : NIH HHS
ID : S10RR027050
Pays : United States
Organisme : NIH HHS
ID : S10 OD020056
Pays : United States
Organisme : NIH HHS
ID : S10OD020056
Pays : United States
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Xenotransplantation. 2013 Nov-Dec;20(6):458-68
pubmed: 24289469
Transplantation. 1976 Dec;22(6):559-67
pubmed: 137560
Proc Natl Acad Sci U S A. 2004 May 11;101(19):7335-40
pubmed: 15123792
Xenotransplantation. 2018 Sep;25(5):e12394
pubmed: 29604134
Transplantation. 2007 Apr 15;83(7):982-8
pubmed: 17460571
Transplantation. 2011 May 15;91(9):968-75
pubmed: 21403591
J Immunol. 1991 Dec 15;147(12):4140-6
pubmed: 1753089
Am J Transplant. 2017 Feb;17(2):353-364
pubmed: 27401926
Xenotransplantation. 2015 Mar-Apr;22(2):85-94
pubmed: 25308416
J Exp Med. 2016 Jan 11;213(1):93-108
pubmed: 26694971
Cold Spring Harb Perspect Med. 2014 Jan 01;4(1):a015529
pubmed: 24384815
Transplant Proc. 2000 Aug;32(5):1047
pubmed: 10936346
Blood. 2007 Feb 15;109(4):1773-81
pubmed: 17023586
Int J Surg. 2015 Nov;23(Pt B):217-222
pubmed: 26231992
Nat Methods. 2018 Aug;15(8):623-630
pubmed: 30065364
J Clin Invest. 1999 Aug;104(3):281-90
pubmed: 10430609
Am J Transplant. 2007 Sep;7(9):2090-7
pubmed: 17640313
Curr Opin Organ Transplant. 2018 Dec;23(6):642-648
pubmed: 30379724
Immunol Rev. 2014 Mar;258(1):241-58
pubmed: 24517437
Xenotransplantation. 2010 Jul-Aug;17(4):300-12
pubmed: 20723202
Hum Immunol. 2018 May;79(5):258-265
pubmed: 29175110
Blood. 2004 May 15;103(10):3964-9
pubmed: 14739221
Nat Med. 2005 Dec;11(12):1295-8
pubmed: 16311604
J Exp Med. 1998 Apr 20;187(8):1335-42
pubmed: 9547344
Int J Surg. 2015 Nov;23(Pt B):223-228
pubmed: 26306769
Am J Transplant. 2005 Dec;5(12):2821-9
pubmed: 16302994
Xenotransplantation. 2003 Mar;10(2):98-106
pubmed: 12588643
Blood. 2017 Feb 23;129(8):959-969
pubmed: 28077418
J Immunol. 2003 Nov 15;171(10):5406-14
pubmed: 14607944
Science. 2002 Feb 8;295(5557):1089-92
pubmed: 11778012
J Immunol. 1984 Jul;133(1):368-75
pubmed: 6609988
Xenotransplantation. 2000 Feb;7(1):58-64
pubmed: 10809058
Am J Pathol. 2008 Jun;172(6):1471-81
pubmed: 18467706
Science. 2003 Jan 17;299(5605):411-4
pubmed: 12493821
Transplant Proc. 1991 Feb;23(1 Pt 1):880-2
pubmed: 1990712
Sci Immunol. 2019 Nov 1;4(41):
pubmed: 31676497
Transplantation. 2001 Jun 15;71(11):1532-42
pubmed: 11435961
Curr Opin Organ Transplant. 2017 Dec;22(6):522-528
pubmed: 28937406
Xenotransplantation. 2011 Jan-Feb;18(1):1-5
pubmed: 21342282
Xenotransplantation. 2001 Nov;8(4):227-38
pubmed: 11737848
Transplant Proc. 1994 Jun;26(3):1197-8
pubmed: 8029884
Transpl Int. 2020 Jan;33(1):30-40
pubmed: 31705678
J Immunol. 1991 Jul 1;147(1):79-85
pubmed: 2051029
Xenotransplantation. 2020 Jan;27(1):e12552
pubmed: 31544995