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Cardiac Xenotransplantation in Nonhuman Primates

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Clinical Xenotransplantation
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Abstract

For many years, exploration of pig heart transplantation in nonhuman primates was carried out after placing the pig heart in a heterotopic position, e.g., in the neck or abdomen, of the recipient. This allowed observations to be made of rejection and of how this could be prevented by immunosuppressive therapy and/or immunomodulation procedures, e.g., anti-pig antibody adsorption. With the development of genetic engineering techniques, and the availability of ever-more sophisticated pigs and novel immunosuppressive agents, e.g., costimulation blockade, survival of the grafts increased from minutes to weeks and months, until some pig hearts were functioning for more than 2 years. However, translation of these improvements to orthotopic heart transplantation was delayed by a high incidence of early graft dysfunction from a non-immunological cause. This problem has been overcome by improved methods of protection of the myocardium from ischemic insult during transplantation. Graft and recipient survival after orthotopic heart transplantation have now increased to 6 months. Nevertheless, ventricular hypertrophy has been observed and may be related to a higher systemic vascular resistance in baboons than in pigs. With the availability of continually improving mechanical assist devices, the selection of patients for the first clinical trial of pig heart transplantation may prove more difficult than that for kidney transplantation.

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Abbreviations

CRP:

Complement-regulatory protein

Gal:

Galactose -α1,3-galactose

GTKO:

α1,3-galactosyltransferase gene-knockout

Neu5Gc:

N-glycolylneuraminic acid

NHP:

Nonhuman primate

TBM:

Thrombomodulin

References

  1. Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38–360. https://doi.org/10.1161/CIR.0000000000000350.

    Article  Google Scholar 

  2. DeSalvatore S, Segreto A, Chiusaroli A, Congiu S, Bizzarri F. The role of xenotransplantation in cardiac transplantation. J Card Surg. 2015;30:111–6.

    Google Scholar 

  3. Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report – 2019; focus theme: donor and recipient size match. J Heart Lung Transplant. 2019;38:1056–66.

    PubMed  PubMed Central  Google Scholar 

  4. Cooper DKC. The case for xenotransplantation. Clin Transpl. 2015;29:288–93.

    Google Scholar 

  5. Czaplicki J, Blonska B, Religa Z. The lack of hyperacute xenogeneic heart transplant rejection in a human. J Heart Lung Transplant. 1992;11(2 Pt 1):393–39. New India Express. 02/1999

    CAS  PubMed  Google Scholar 

  6. New India Express. 1999.

    Google Scholar 

  7. Lambrigts D, Sachs DH, Cooper DKC. Discordant organ xenotransplantation in primates: world experience and current status. Transplantation. 1998;66:547–61.

    CAS  PubMed  Google Scholar 

  8. Cooper DKC, Satyananda V, Ekser B, et al. Progress in pig-to-nonhuman primate transplantation models (1998–2013): a comprehensive review of the literature. Xenotransplantation. 2014;21:397–419.

    PubMed  PubMed Central  Google Scholar 

  9. Lexer G, Cooper DKC, Rose AG, et al. Hyperacute rejection in a discordant (pig to baboon) cardiac xenograft model. J Heart Transplant. 1986;5:411–8.

    CAS  PubMed  Google Scholar 

  10. Rose AG, Cooper DKC, Human PA, Reichenspurner H, Reichart B. Histopathology of hyperacute rejection of the heart: experimental and clinical observations in allografts and xenografts. J Heart Lung Transplant. 1991;10:223–34.

    CAS  PubMed  Google Scholar 

  11. Cooper DKC, Human PA, Lexer G, et al. Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon. J Heart Transplant. 1988;7:238–46.

    CAS  PubMed  Google Scholar 

  12. Leventhal JR, Dalmasso AP, Cromwell JW, et al. Prolongation of cardiac xenograft survival by depletion of complement. Transplantation. 1993;55:857–65; discussion 865–856.

    CAS  PubMed  Google Scholar 

  13. Cozzi E, Yannoutsos N, Langford GA, Pino-Chavez G, Wallwork J, White DJG. Effects of transgenic expression of human decay accelerating factor on the inhibition of hyperacute rejection of pig organs. In: Cooper DKC, Kemp E, Platt JL, White DJG, editors. Xenotransplantation – the transplantation of organs and tissues between species. Berlin: Springer; 1997. p. 665–82.

    Google Scholar 

  14. Vial CM, Ostlie DJ, Bhatti FN, et al. Life supporting function for over one month of a transgenic porcine heart in a baboon. J Heart Lung Transplant. 2000;19:224–9.

    CAS  PubMed  Google Scholar 

  15. Kuwaki K, Tseng YL, Dor FJ, et al. Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med. 2005;11:29–31.

    CAS  PubMed  Google Scholar 

  16. Tseng YL, Kuwaki K, Dor FJ, et al. α 1,3-galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching six months. Transplantation. 2005;80:1493–500.

    CAS  PubMed  Google Scholar 

  17. Bühler L, Basker M, Alwayn IPJ, et al. Coagulation and thrombotic disorders associated with pig organ and hematopoietic cell transplantation in nonhuman primates. Transplantation. 2000;70:1323–31.

    PubMed  Google Scholar 

  18. Mohiuddin MM, Singh AK, Corcoran PC, et al. Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation. J Thorac Cardiovasc Surg. 2014;148:1106–13; discussion 1113–1104.

    PubMed  PubMed Central  Google Scholar 

  19. Mohiuddin MM, Singh AK, Corcoran PC, et al. Role of anti-CD40 antibody-mediated costimulation blockade on non-Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon model. Xenotransplantation. 2014;21:35–45.

    PubMed  Google Scholar 

  20. Cooper DKC. Experimental development of cardiac transplantation. Br Med J. 1968;4:174–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Barnard CN, Losman JG. Left ventricular bypass. S Afr Med J. 1975;49:303–12.

    CAS  PubMed  Google Scholar 

  22. Novitzky D, Cooper DKC, Barnard CN. The surgical technique of heterotopic heart transplantation. Ann Thorac Surg. 1983;36:476–82.

    CAS  PubMed  Google Scholar 

  23. Bauer A, Postrach J, Thormann M, et al. First experience with heterotopic thoracic pig-to-baboon cardiac xenotransplantation. Xenotransplantation. 2010;17:243–9.

    PubMed  Google Scholar 

  24. Abicht JM, Mayr T, Reichart B, et al. Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique. Xenotransplantation. 2015;22:427–42.

    PubMed  Google Scholar 

  25. Mayr T, Bauer A, Reichart B, et al. Hemodynamic and perioperative management in two different preclinical pig-to-baboon cardiac xenotransplantation models. Xenotransplantation. 2017;24(3). https://doi.org/10.1111/xen.12295.

  26. Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur hospital, Cape town. S Afr Med J. 1967;41:1271–4.

    CAS  PubMed  Google Scholar 

  27. Cooper DKC, Keogh AM, Brink J, et al. Report of the xenotransplantation advisory committee of the international society for heart and lung transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases. J Heart Lung Transplant. 2000;19:1125–65.

    CAS  PubMed  Google Scholar 

  28. Chen G, Qian H, Starzl T, et al. Acute rejection is associated with antibodies to non-gal antigens in baboons using gal-knockout pig kidneys. Nat Med. 2005;11:1295–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. McGregor CGA, Davies WR, Oi K, et al. Cardiac xenotransplantation: recent preclinical progress with 3-month median survival. J Thorac Cardiovasc Surg. 2005;130:844–51.

    PubMed  Google Scholar 

  30. Buhler 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;69:2296–304.

    CAS  PubMed  Google Scholar 

  31. 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. https://doi.org/10.1038/ncomms11138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ezzelarab MB, Ekser B, Echeverri G, et al. Costimulation blockade in pig artery patch xenotransplantation – a simple model to monitor the adaptive immune response in nonhuman primates. Xenotransplantation. 2012;19:221–32.

    PubMed  PubMed Central  Google Scholar 

  33. Phelps CJ, Ball SF, Vaught TD, et al. Production and characterization of transgenic pigs expressing porcine ctla4-ig. Xenotransplantation. 2009;16:477–85.

    PubMed  Google Scholar 

  34. Hara H, Witt W, Crossley T, et al. Human dominant-negative class ii transactivator transgenic pigs – effect on the human anti-pig T-cell immune response and immune status. Immunology. 2013;140:39–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wilhite T, Ezzelarab C, Hara H, et al. The effect of gal expression on pig cells on the human T-cell xenoresponse. Xenotransplantation. 2012;19:56–63.

    PubMed  PubMed Central  Google Scholar 

  36. Ezzelarab MB, Ayares D, Cooper DKC. Transgenic expression of human CD46: does it reduce the primate T-cell response to pig endothelial cells? Xenotransplantation. 2015;22:487–9.

    PubMed  Google Scholar 

  37. Mohiuddin MM, Reichart B, Byrne GW, McGregor CGA. Current status of pig heart xenotransplantation. Int J Surg. 2015;23(Pt B):234–9.

    PubMed  PubMed Central  Google Scholar 

  38. Byrne GW, Du Z, Sun Z, Asmann YW, McGregor CGA. Changes in cardiac gene expression after pig-to-primate orthotopic xenotransplantation. Xenotransplantation. 2011;18:14–27.

    PubMed  Google Scholar 

  39. Byrne GW, McGregor CGA. Cardiac xenotransplantation: progress and challenges. Curr Opin Organ Transplant. 2012;17:148–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. McGregor CGA, Byrne GW. Porcine to human heart transplantation: is clinical application now appropriate? J Immunol Res. 2017;2017:2534653.

    PubMed  PubMed Central  Google Scholar 

  41. Novitzky D, Human PA, Cooper DKC. Inotropic effect of triiodothyronine following myocardial ischaemia and cardiopulmonary bypass: an experimental study in pigs. Ann Thorac Surg. 1988;45:50–5.

    CAS  PubMed  Google Scholar 

  42. Novitzky D, Human PA, Cooper DKC. Effect of triiodothyronine (T3) on myocardial high energy phosphates and lactate after ischemia and cardiopulmonary bypass. An experimental study in baboons. J Thorac Cardiovasc Surg. 1988;96:600–7.

    CAS  PubMed  Google Scholar 

  43. Novitzky D, Cooper DKC, Swanepoel A. Inotropic effect of triiodothyronine (T3) in low cardiac output following cardioplegic arrest and cardiopulmonary bypass: an initial experience in patients undergoing open heart surgery. Eur J Cardiothorac Surg. 1989;3:140–5.

    CAS  PubMed  Google Scholar 

  44. Iwase H, Ekser B, Satyananda V, Ezzelarab M, Cooper DKC. Plasma free triiodothyronine (fT3) levels in baboons undergoing pig organ transplantation: relevance to early recovery of organ function. Xenotransplantation. 2014;21:582–3.

    PubMed  PubMed Central  Google Scholar 

  45. Iwase H, Ekser B, Hara H, et al. Thyroid hormone: relevance to xenotransplantation. Xenotransplantation. 2016;23:293–9.

    PubMed  PubMed Central  Google Scholar 

  46. Längin M, Mayr T, Reichart B, et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature. 2018;564(7736):430–3.

    PubMed  Google Scholar 

  47. Steen S, Paskevicius A, Liao Q, Sjöberg T. Safe orthotopic transplantation of hearts harvested 24 hours after brain death and preserved for 24 hours. Scand Cardiovasc J. 2016;50:193–200.

    PubMed  PubMed Central  Google Scholar 

  48. Yamamoto T, Hara H, Iwase H, et al. The final obstacle to a successful pre-clinical xenotransplantation. Xenotransplantation. 2020. In press.

    Google Scholar 

  49. Ibrahim Z, Busch J, Awwad M, Wagner R, Wells K, Cooper DKC. Selected physiologic compatibilities and incompatibilities between human and porcine organ systems. Xenotransplantation. 2006;13:488–99.

    PubMed  Google Scholar 

  50. Iwase H, Klein E, Cooper DKC. Physiologic aspects of pig kidney transplantation in nonhuman primates. Comp Med. 2018;68:332–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Iwase H, Ekser B, Satyananda V, et al. Pig-to-baboon heterotopic heart transplantation – exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens. Xenotransplantation. 2015;22:211–20.

    PubMed  PubMed Central  Google Scholar 

  52. Iwase H, Hara H, Ezzelarab M, et al. Immunological and physiologic observations in baboons with life-supporting genetically-engineered pig kidney grafts. Xenotransplantation. 2017;24. https://doi.org/10.1111/xen.12293.

  53. Murthy R, Bajona P, Bhama JK, Cooper DKC. Heart xenotransplantation: historical background, experimental progress, and clinical prospects. Ann Thorac Surg. 2016;101:1605–13.

    PubMed  Google Scholar 

  54. Cooper DKC, Tseng YL, Saidman SL. Alloantibody and xenoantibody cross-reactivity in transplantation. Transplantation. 2004;77:1–5.

    CAS  PubMed  Google Scholar 

  55. Li Q, Hara H, Zhang Z, Breimer ME, Wang Y, Cooper DKC. Is sensitization to pig antigens detrimental to subsequent allotransplantation? Xenotransplantation. 2018;25:e12393. https://doi.org/10.1111/xen.12393.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The author gratefully recognizes grant funding over many years from the NIH NIAID, and from Revivicor, Blacksburg, VA, and United Therapeutics, Silver Spring, MD.

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The author reports no conflict of interest.

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Correspondence to David K. C. Cooper .

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Cooper, D.K.C. (2020). Cardiac Xenotransplantation in Nonhuman Primates. In: Cooper, D.K.C., Byrne, G. (eds) Clinical Xenotransplantation. Springer, Cham. https://doi.org/10.1007/978-3-030-49127-7_6

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  • DOI: https://doi.org/10.1007/978-3-030-49127-7_6

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