Pig-to-human heart xenotransplantation in two recently deceased human recipients.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
20
01
2023
accepted:
26
06
2023
medline:
17
8
2023
pubmed:
25
7
2023
entrez:
24
7
2023
Statut:
ppublish
Résumé
Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.
Identifiants
pubmed: 37488288
doi: 10.1038/s41591-023-02471-9
pii: 10.1038/s41591-023-02471-9
doi:
Substances chimiques
Antibodies
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1989-1997Subventions
Organisme : NCI NIH HHS
ID : U01 CA214195
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Garry, D. J., Weiner, J. I., Greising, S. M., Garry, M. G. & Sachs, D. H. Mechanisms and strategies to promote cardiac xenotransplantation. J. Mol. Cell. Cardiol. 172, 109–119 (2022).
doi: 10.1016/j.yjmcc.2022.07.013
pubmed: 36030840
Luepker, R. V. Epidemiology of heart failure. In Congestive Heart Failure and Cardiac Transplantation (eds. Garry, D. J., Wilson, R. F. & Vlodaver, Z.) 93–102 (Springer International Publishing, 2017). https://doi.org/10.1007/978-3-319-44577-9_6
Heidenreich, P. A. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145, e876–e894 (2022).
pubmed: 35363500
Virani, S. S. et al. Heart disease and stroke statistics – 2020 update: a report from the American Heart Association. Circulation 141, e139–e596 (2020).
doi: 10.1161/CIR.0000000000000757
pubmed: 31992061
Organ Procurement and Transplantation Network. National data. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/
Reichart, B. et al. Pathways to clinical cardiac xenotransplantation. Transplantation 105, 1930–1943 (2021).
doi: 10.1097/TP.0000000000003588
pubmed: 33350675
Platt, J. L., Cascalho, M. & Piedrahita, J. A. Xenotransplantation: progress along paths uncertain from models to application. ILAR J. 59, 286–308 (2018).
doi: 10.1093/ilar/ily015
pubmed: 30541147
pmcid: 6808066
Llore, N. P., Bruestle, K. A. & Griesemer, A. Xenotransplantation tolerance: applications for recent advances in modified swine. Curr. Opin. Organ Transplant. 23, 642–648 (2018).
doi: 10.1097/MOT.0000000000000585
pubmed: 30379724
pmcid: 7010353
Hryhorowicz, M., Zeyland, J., Słomski, R. & Lipiński, D. Genetically modified pigs as organ donors for xenotransplantation. Mol. Biotechnol. 59, 435–444 (2017).
doi: 10.1007/s12033-017-0024-9
pubmed: 28698981
pmcid: 5617878
Montgomery, R. A. et al. Results of two cases of pig-to-human kidney xenotransplantation. N. Engl. J. Med. 386, 1889–1898 (2022).
doi: 10.1056/NEJMoa2120238
pubmed: 35584156
Montgomery, R. A., Mehta, S. A., Parent, B. & Griesemer, A. Next steps for the xenotransplantation of pig organs into humans. Nat. Med. 28, 1533–1536 (2022).
doi: 10.1038/s41591-022-01896-y
pubmed: 35941375
Sykes, M. Developing pig-to-human organ transplants. Science 378, 135–136 (2022).
doi: 10.1126/science.abo7935
pubmed: 36227981
pmcid: 9671127
Griffith, B. P. et al. Genetically modified porcine-to-human cardiac xenotransplantation. N. Engl. J. Med. 387, 35–44 (2022).
doi: 10.1056/NEJMoa2201422
pubmed: 35731912
pmcid: 10361070
Goradia, S., Sardaneh, A. A., Narayan, S. W., Penm, J. & Patanwala, A. E. Vasopressor dose equivalence: a scoping review and suggested formula. J. Crit. Care 61, 233–240 (2021).
doi: 10.1016/j.jcrc.2020.11.002
pubmed: 33220576
Kagan, C. et al. Abstract 12072: EKG appearance and evolution of baseline EKG-characteristics in the worldwide first genetically modified porcine-to-human xenotransplant (‘pig heart-in-human body’). Circulation 146(Suppl. 1), A12072 (2022).
Paradis, K. et al. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. Science 285, 1236–1241 (1999).
doi: 10.1126/science.285.5431.1236
pubmed: 10455044
Denner, J. Porcine endogenous retroviruses (PERVs) and xenotransplantation: screening for transmission in several clinical trials and in experimental models using non-human primates. Ann. Transplant. 8, 39–48 (2003).
pubmed: 15114938
Nishitai, R. et al. Absence of PERV infection in baboons after transgenic porcine liver perfusion. J. Surg. Res. 124, 45–51 (2005).
doi: 10.1016/j.jss.2004.09.006
pubmed: 15734478
Heneine, W. et al. No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts. Lancet 352, 695–699 (1998).
doi: 10.1016/S0140-6736(98)07145-1
pubmed: 9728986
Valdes-Gonzalez, R., Dorantes, L. M., Bracho-Blanchet, E., Rodríguez-Ventura, A. & White, D. J. G. No evidence of porcine endogenous retrovirus in patients with type 1 diabetes after long-term porcine islet xenotransplantation. J. Med. Virol. 82, 331–334 (2010).
doi: 10.1002/jmv.21655
pubmed: 20029803
Di Nicuolo, G. et al. Long-term absence of porcine endogenous retrovirus infection in chronically immunosuppressed patients after treatment with the porcine cell-based Academic Medical Center bioartificial liver. Xenotransplantation 17, 431–439 (2010).
doi: 10.1111/j.1399-3089.2010.00617.x
pubmed: 21158944
Längin, M. et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 564, 430–433 (2018).
doi: 10.1038/s41586-018-0765-z
pubmed: 30518863
Reichart, B. et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation? J. Heart Lung Transplant. 39, 751–757 (2020).
doi: 10.1016/j.healun.2020.05.004
pubmed: 32527674
Goh, B. K., Chedid, M. F., Gloor, J. M., Raghavaiah, S. & Stegall, M. D. The impact of terminal complement blockade on the efficacy of induction with polyclonal rabbit antithymocyte globulin in living donor renal allografts. Transpl. Immunol. 27, 95–100 (2012).
doi: 10.1016/j.trim.2012.07.002
pubmed: 22813834
Mohiuddin, M. M. 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. 7, 11138 (2016).
doi: 10.1038/ncomms11138
pubmed: 27045379
pmcid: 4822024
Pierson, R. N. et al. Progress toward cardiac xenotransplantation. Circulation 142, 1389–1398 (2020).
doi: 10.1161/CIRCULATIONAHA.120.048186
pubmed: 33017208
pmcid: 7990044
Griesemer, A. D. et al. Upregulation of CD59: potential mechanism of accommodation in a large animal model. Transplantation 87, 1308–1317 (2009).
doi: 10.1097/TP.0b013e3181a19afc
pubmed: 19424030
pmcid: 2772119
Kroshus, T. J. et al. Expression of human CD59 in transgenic pig organs enhances organ survival in an ex vivo xenogeneic perfusion model. Transplantation 61, 1513–1521 (1996).
doi: 10.1097/00007890-199605270-00018
pubmed: 8633381
Wang, X. et al. CD47 blockade reduces ischemia/reperfusion injury in donation after cardiac death rat kidney transplantation. Am. J. Transplant. 18, 843–854 (2018).
doi: 10.1111/ajt.14523
pubmed: 28975767
Mohiuddin, M. M. et al. Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months. Xenotransplantation 29, e12744 (2022).
doi: 10.1111/xen.12744
pubmed: 35357044
pmcid: 10325874
Byrne, G. W. & McGregor, C. G. Cardiac Xenotransplantation: Progress and Challenges. Curr Opin Organ Transplant 17, 148–154 (2012).
doi: 10.1097/MOT.0b013e3283509120
pubmed: 22327911
pmcid: 3326642
Mehta, S. A., Saharia, K. K., Nellore, A., Blumberg, E. A. & Fishman, J. A. Infection and clinical xenotransplantation: guidance from the Infectious Disease Community of Practice of the American Society of Transplantation. Am. J. Transplant. 23, 309–315 (2023).
doi: 10.1016/j.ajt.2022.12.013
pubmed: 36695690
Caplan, A. Bioethics of organ transplantation. Cold Spring Harb. Perspect. Med. 4, a015685 (2014).
doi: 10.1101/cshperspect.a015685
pubmed: 24478386
pmcid: 3935394
Parent, B. et al. The ethics of testing and research of manufactured organs on brain-dead/recently deceased subjects. J. Med. Ethics 46, 199–204 (2020).
doi: 10.1136/medethics-2019-105674
pubmed: 31563872
Walker, R. L., Juengst, E. T., Whipple, W. & Davis, A. M. Genomic research with the newly dead: a crossroads for ethics and policy. J. Law Med. Ethics 42, 220–231 (2014).
doi: 10.1111/jlme.12137
pubmed: 25040385
pmcid: 4378691
Pentz, R. D. et al. Ethics guidelines for research with the recently dead. Nat. Med. 11, 1145–1149 (2005).
doi: 10.1038/nm1105-1145
pubmed: 16270065
Yasko, L. L., Wicclair, M. & DeVita, M. A. Committee for Oversight of Research Involving the Dead (CORID): insights from the first year. Camb. Q. Healthc. Ethics 13, 327–337 (2004).
doi: 10.1017/S096318010413404X
pubmed: 15552324
Rautaharju, P. M., Surawicz, B. & Gettes, L. S. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram. Circulation 119, e241–e250 (2009).
doi: 10.1161/CIRCULATIONAHA.108.191096
pubmed: 19228821
Kossmann, C. E. The normal electrocardiogram. Circulation 8, 920–936 (1953).
doi: 10.1161/01.CIR.8.6.920
pubmed: 13106913
Clauss, S. et al. Animal models of arrhythmia: classic electrophysiology to genetically modified large animals. Nat. Rev. Cardiol. 16, 457–475 (2019).
doi: 10.1038/s41569-019-0179-0
pubmed: 30894679
Berry, G. J. et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J. Heart Lung Transplant. 32, 1147–1162 (2013).
doi: 10.1016/j.healun.2013.08.011
pubmed: 24263017
Denner, J. Can antiretroviral drugs be used to treat porcine endogenous retrovirus (PERV) infection after xenotransplantation? Viruses 9, E213 (2017).
doi: 10.3390/v9080213