The final obstacle to successful pre-clinical xenotransplantation?
baboon
genetically engineered
pig
xenoantigen
xenotransplantation
Journal
Xenotransplantation
ISSN: 1399-3089
Titre abrégé: Xenotransplantation
Pays: Denmark
ID NLM: 9438793
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
24
01
2020
revised:
27
03
2020
accepted:
07
04
2020
pubmed:
26
6
2020
medline:
17
8
2021
entrez:
26
6
2020
Statut:
ppublish
Résumé
Genetically engineered pigs are now available for xenotransplantation in which all three known carbohydrate xenoantigens, against which humans have natural antibodies, have been deleted (triple-knockout [TKO] pigs). Furthermore, multiple human transgenes have been expressed in the TKO pigs, all of which are aimed at protecting the cells from the human immune response. Many human sera demonstrate no or minimal antibody binding to, and little or no cytotoxicity of, cells from these pigs, and this is associated with a relatively low T-cell proliferative response. Unfortunately, baboons and other Old World NHPs have antibodies against TKO pig cells, apparently directed to a fourth xenoantigen that appears to be exposed after TKO. In our experience, most, if not all, humans do not have natural antibodies against this fourth xenoantigen. This discrepancy between NHPs and humans is providing a hurdle to successful translation of pig organ transplantation into the clinic, and making it difficult to provide pre-clinical data that support initiation of a clinical trial. The potential methods by which this obstacle might be overcome are discussed. We conclude that, whatever currently available genetically engineered pig is selected for the final pre-clinical studies, this may not be the optimal pig for clinical trials.
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
e12596Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Higginbotham L, Mathews D, Breeden CA, et al. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation. 2015;22:221-230.
Iwase H, Liu H, Wijkstrom M, et al. Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date. Xenotransplantation. 2015;22:302-309.
Iwase H, Hara H, Ezzelarab M, et al. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation. 2017;24:e12293.
Adams AB, Kim SC, Martens GR, et al. Xenoantigen deletion and chemical immunosuppression can prolong renal xenograft survival. Ann Surg. 2018;268:564-573.
Längin M, Mayr T, Reichart B, et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature. 2018;564:430-433.
Estrada J, Martens G, Li P, et al. Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/beta4GALNT2 genes. Xenotransplantation. 2015;22:194-202.
Li QI, Shaikh S, Iwase H, et al. Carbohydrate antigen expression and anti-pig antibodies in New World capuchin monkeys: relevance to studies of xenotransplantation. Xenotransplantation. 2019;26:e12498.
Cooper D, Ezzelarab M, Iwase H, Hara H. Perspectives on the optimal genetically-engineered pig in 2018 for initial clinical trials of kidney or heart xenotransplantation. Transplantation. 2018;102:1974-1982.
Cooper D, Hara H, Iwase H, et al. Justification of specific genetic modifications in pigs for clinical kidney or heart xenotransplantation. Xenotransplantation. 2019;26:e12516.
Yue Y, Kan Y, Xu W, et al. Extensive mammalian germline genome engineering. bioRxiv. 2019; https://doi.org/10.1101/2019.12.17.876862
Li Q, Hara H, Banks C, et al. Anti-pig antibody in infants: can a genetically engineered pig heart bridge to allotransplantation? Ann Thorac Surg. 2020;109(4):1268-1273.
Hara H, Long C, Lin YJ, et al. In vitro investigation of pig cells for resistance to human antibody-mediated rejection. Transplant Int. 2008;21:1163-1174.
Azimzadeh AM, Kelishadi SS, Ezzelarab MB, et al. Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein. Xenotransplantation. 2015;22:310-316.
McGregor CGA, Ricci D, Miyagi N, et al. Human cd55 expression blocks hyperacute rejection and restricts complement activation in gal knockout cardiac xenografts. Transplantation. 2012;93:686-692.
Bühler L, Awwad M, Basker M, et al. High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response. Transplantation. 2000;69:2296-2304.
Mohiuddin MM, Singh AK, Corcoran PC, et al. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46. hTBM pig-to-primate cardiac xenograft. Nat Commun. 2016;7:11138.
Yamamoto T, Hara H, Foote J, et al. Life-supporting kidney xenotransplantation from genetically-engineered pigs in baboons: a comparison of two immunosuppressive regimens. Transplantation. 2019;103(10):2090-2104.
Novitzky D, Wicomb W, Cooper D. Pathophysiology of brain death and effects of hormonal therapy in large animal models. In: Novitzky D, Cooper D, eds. The Brain-Dead Organ Donor: Pathophysiology and Management. New York: Springer; 2013:65-90.
Barklin A, Hvas C, Toennesen E. The inflammatory response to brain death. In: Novitzky D, Cooper D, eds. The Brain-Dead Organ Donor: Pathophysiology and Management. New York: Springer; 2013:107-120.
Iwase H, Klein E, Cooper D. Physiological aspects of pig kidney transplantation in primates. Comp Med. 2018;68:332-340.
Tanabe T, Watanabe H, Shah JA, et al. Role of intrinsic (graft) versus extrinsic (host) factors in the growth of transplanted organs following allogeneic and xenogeneic transplantation. Am J Transplant. 2017;17:1778-1790.
Yamamoto Takayuki, Ladowski Joseph M, Bikhet Mohamed, Cooper David KC, Hara Hidetaka. Efficacy of ATG and Rituximab in capuchin monkeys (a New World monkey) - an in vitro study relevant to xenotransplantation. Xenotransplantation. 2020;In press.
Cooper D, Human P, Lexer G, et al. Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon. J Heart Transplant. 1988;7:238-246.
Watts A, Foley A, Awwad M, et al. Plasma perfusion by apheresis through a Gal immunoaffinity column successfully depletes anti-Gal antibody: experience with 320 aphereses in baboons. Xenotransplantation. 2000;7:181-185.
Platt JL. A perspective on xenograft rejection and accommodation. Immunol Rev. 1994;141:127-149.
de Mattos G, Barbosa M, Cascalho M, Platt J. Accommodation in ABO-incompatible organ transplants. Xenotransplantation. 2018;25:e12418.
Alexandre G, Squifflet J, De Bruyere M, et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc. 1987;19:4538-4542.
Alexandre G. From ABO-incompatible human kidney transplantation to xenotransplantation. Xenotransplantation. 2004;11:233-236.
West L. Targeting antibody-mediated rejection in the setting of ABO-incompatible infant heart transplantation: graft accommodation vs. B cell tolerance. Curr Drug Targets Cardiovasc Haematol Disord. 2005;5:223-232.
Gao B, Long C, Lee W, et al. Anti-Neu5Gc and anti-non-Neu5Gc antibodies in healthy humans. PLoS One. 2017;12(7):e0180768.