Advertisement

Xenotransplantation

  • J. A. Shah
  • B. Ekser
  • P. A. Vagefi
Chapter
First Online:

Abstract

Shortages in the number of available donor organs continue to force the transplant community to seek alternative options in an effort to meet the high demand. Cross species, or xenotransplantation, using swine as potential donors, has long been hypothesized as a potential attractive strategy for solving the organ shortage crisis due to the supply of available donors, as well as anatomical and physiological similarities between swine and humans. Early studies with wild-type swine donors were limited due to shortened survival as a result of acute humoral xenograft rejection due to circulating preformed antibodies. The eventual development of α-1,3-galactosyltransferase knock-out swine donors in the early 2000s has been critical in advancing preclinical xenotransplantation research, and more recently through significant improvements in genetic engineering technology such as CRISPR/Cas9, the development of multitransgenic swine donors has allowed xenotransplantation to progress closer to becoming a clinical reality. Here, we provide a brief overview of early clinical xenotransplantation experience, followed by major technological advances and current barriers to solid organ (kidney, liver, heart, and lung) and islet cell xenotransplantation.

This is a preview of subscription content, log in to check access.

References

  1. 1.
    OPTN Stats OPTN. (2016). Organ Procurement and Transplantation Network. http://optn.transplant.hrsa.gov. Last accessed on 28 Mar 2016.
  2. 2.
    Cooper, D. K. C., Gollackner, B., & Sachs, D. H. (2002). Will the pig solve the transplantation backlog? Annual Review of Medicine, 53(53), 133–147.CrossRefPubMedGoogle Scholar
  3. 3.
    Ekser, B., Ezzelarab, M., Hara, H., Van Der Windt, D. J., Wijkstrom, M., Bottino, R., et al. (2012). Clinical xenotransplantation: The next medical revolution? Lancet, 379(9816), 672–683.CrossRefPubMedGoogle Scholar
  4. 4.
    Ibrahim, Z., Busch, J., Awwad, M., Wagner, R., Wells, K., & Cooper, D. K. C. (2006). Selected physiologic compatibilities and incompatibilities between human and porcine organ systems. Xenotransplantation, 13(6), 488–499.CrossRefPubMedGoogle Scholar
  5. 5.
    Sachs, D. H. (1994). The pig as a xenograft donor. Pathologie Biologie (Paris), 42(3), 217–219.Google Scholar
  6. 6.
    Editorial. (1999). US guidelines on xenotransplantation. Nature Medicine, 5(5), 465.CrossRefGoogle Scholar
  7. 7.
    Reemtsma, K., Mccracken, B. H., Schlegel, J. U., & Pearl, M. (1964). Heterotransplantation of the kidney: Two clinical experiences. Science, 143(3607), 700–702.CrossRefPubMedGoogle Scholar
  8. 8.
    Hardy, J. D., Kurrus, F. D., Chavez, C. M., Neely, W. A., Eraslan, S., Turner, M. D., et al. (1964). Heart transplantation in man. Developmental studies and report of a case. Journal of the American Medical Association, 188(13), 1132–1140.PubMedGoogle Scholar
  9. 9.
    Starzl, T. E., Fung, J., Tzakis, A., Todo, S., Demetris, A. J., Marino, I. R., et al. (1993). Baboon-to-human liver transplantation. Lancet, 341(8837), 65–71.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lai, L., Kolber-Simonds, D., Park, K. W., Cheong, H. T., Greenstein, J. L., Im, G. S., et al. (2002). Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science, 295(5557), 1089–1092.CrossRefPubMedGoogle Scholar
  11. 11.
    Ekser, B., Rigotti, P., Gridelli, B., & Cooper, D. K. C. (2009). Xenotransplantation of solid organs in the pig-to-primate model. Transplant Immunology, 21(2), 87–92.CrossRefPubMedGoogle Scholar
  12. 12.
    Byrne, G. W., McGregor, C. G. A., & Breimer, M. E. (2015). Recent investigations into pig antigen and anti-pig antibody expression. International Journal of Surgery, 23, 223–228.CrossRefPubMedGoogle Scholar
  13. 13.
    Azimzadeh, A. M., Byrne, G. W., Ezzelarab, M., Welty, E., Braileanu, G., Cheng, X., et al. (2008). Development of a consensus protocol to quantify primate anti-non-gal xenoreactive antibodies using pig aortic endothelial cells. Xenotransplantation, 21(6), 555–566.CrossRefGoogle Scholar
  14. 14.
    Butler, J. R., Ladowski, J. M., Martens, G. R., Tector, M., & Tector, A. J. (2015). Recent advances in genome editing and creation of genetically modified pigs. International Journal of Surgery, 23, 217–222.CrossRefPubMedGoogle Scholar
  15. 15.
    Mali, P., Esvelt, K. M., & Church, G. M. (2013). Cas9 as a versatile tool for engineering biology. Nature Methods, 10(10), 957–963.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Feng, W., Dai, Y., Mou, L., Cooper, D. K. C., Shi, D., & Cai, Z. (2015). The potential of the combination of CRISPR/Cas9 and pluripotent stem cells to provide human organs from chimaeric pigs. International Journal of Molecular Sciences, 16(3), 6545–6556.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Li, P., Estrada, J. L., Burlak, C., Montgomery, J., Butler, J. R., Santos, R. M., et al. (2015). Efficient generation of genetically distinct pigs in a single pregnancy using multiplexed single-guide RNA and carbohydrate selection. Xenotransplantation, 22(1), 20–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Cooper, D. K. C., Ekser, B., & Tector, A. J. (2015). Immunobiological barriers to xenotransplantation. International Journal of Surgery, 23, 211–216.CrossRefPubMedGoogle Scholar
  19. 19.
    Ramsoondar, J., Vaught, T., Ball, S., Mendicino, M., Monahan, J., Jobst, P., et al. (2009). Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs. Xenotransplantation, 16(3), 164–180.CrossRefPubMedGoogle Scholar
  20. 20.
    Dieckhoff, B., Petersen, B., Kues, W. A., Kurth, R., Niemann, H., & Denner, J. (2008). Knockdown of porcine endogenous retrovirus (PERV) expression by PERV-specific shRNA in transgenic pigs. Xenotransplantation, 15(1), 36–45.CrossRefPubMedGoogle Scholar
  21. 21.
    Yang, L., Güell, M., Niu, D., George, H., Lesha, E., Grishin, D., et al. (2015 Nov 27). Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science, 350(6264), 1101–1104.CrossRefPubMedGoogle Scholar
  22. 22.
    Lambrigts, D., Sachs, D. H., & Cooper, D. K. (1998 Sep 15). Discordant organ xenotransplantation in primates: World experience and current status. Transplantation, 66(5), 547–561.CrossRefPubMedGoogle Scholar
  23. 23.
    Baldana, N., Rigotti, P., Calabrese, F., Cadrobbi, R., Dedja, A., Iacopetti, I., et al. (2004). Ureteral stenosis in HDAF pig-to-primate renal xenotransplantation: A phenomenon related to immunological events? American Journal of Transplantation, 4(4), 475–481.CrossRefGoogle Scholar
  24. 24.
    Yamada, K., Yazawa, K., Shimizu, A., Iwanaga, T., Hisashi, Y., Nuhn, M., et al. (2005). Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1,3-galactosyltransferase gene-knockout donors and the Cotransplantation of vascularized Thymic tissue. Nature Medicine, 11(1), 32–34.CrossRefPubMedGoogle Scholar
  25. 25.
    Buhler, L., Awwad, M., Basker, M., Gojo, S., Watts, A., Treter, S., et al. (2000). High-dose porcine hematopoeitic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response. Transplantation, 69(11), 2296–2304.CrossRefPubMedGoogle Scholar
  26. 26.
    Iwase, H., Ekser, B., Satyananda, V., Bhama, J., Hara, H., Ezzelarab, M., et al. (2015). Pig-to-baboon heterotopic heart transplantation – exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens. Xenotransplantation, 22, 211–220.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shimizu, A., Yamada, K., Yamamoto, S., Lavelle, J. M., Barth, R. N., Robson, S. C., et al. (2005). Thrombotic microangiopathic glomerulopathy in human decay accelerating factor-transgenic swine-to-baboon kidney xenografts. Journals of the American Society of Nephrology, 16(9), 2732–2745.CrossRefGoogle Scholar
  28. 28.
    Ierino, F. L., Kozlowski, T., Siegel, J. B., Shimizu, A., Colvin, R. B., Banerjee, P. T., et al. (1998). Disseminated intravascular coagulation in association with the delayed rejection of pig-to-baboon renal xenografts. Transplantation, 66(11), 1439–1450.CrossRefPubMedGoogle Scholar
  29. 29.
    Miwa, Y., Yamamoto, K., Onishi, A., Iwamoto, M., Yazaki, S., Haneda, M., et al. (2010). Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation. Xenotransplantation, 17(1), 26–37.CrossRefPubMedGoogle Scholar
  30. 30.
    Iwase, H., Ezzelarab, M. B., Ekser, B., & Cooper, D. K. C. (2014). The role of platelets in coagulation dysfunction in xenotransplantation, and therapeutic options. Xenotransplantation, 21(3), 201–220.CrossRefPubMedGoogle Scholar
  31. 31.
    Higginbotham, L., Mathews, D., Breeden, C. A., Song, M., Farris, A. B., Larsen, C. P., et al. (2015). Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation, 22, 221–230.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Iwase, H., Liu, H., Wijkstrom, M., Zhou, H., Singh, J., Hara, H., et al. (2015). Pig kidney graft survival in a baboon for 136 days: Longest life-supporting organ graft survival to date. Xenotransplantation, 22(4), 302–309.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tasaki, M., Shimizu, A., Hanekamp, I., Torabi, R., Villani, V., & Yamada, K. (2014). Rituximab treatment prevents the early development of proteinuria following pig-to-baboon xeno-kidney transplantation. Journals of the American Society of Nephrology, 25(4), 737–744.CrossRefGoogle Scholar
  34. 34.
    Soin, B., Ostlie, D., Cozzi, E., Smith, K. G., Bradley, J. R., Vial, C., et al. (2000). Growth of porcine kidneys in their native and xenograft environment. Xenotransplantation, 7(2), 96–100.CrossRefPubMedGoogle Scholar
  35. 35.
    Higginbotham, L., Mathews, D., Stephenson, A., Breeden, C., Larsen, C., & For, M. (2015). Long-term survival of pig-to-primate renal xenotransplant using costimulation-blockade immunosuppression. Xenotransplantation, 22(Supplement:S45).CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Calne, R. Y., White, H. J., Herbertson, B. M., Millard, P. R., Davis, D. R., Salaman, J. R., et al. (1968). Pig-to-baboon liver xenografts. Lancet, 1(7553), 1176–1178.CrossRefPubMedGoogle Scholar
  37. 37.
    Ramirez, P., Chavez, R., Majado, M., Munitiz, V., Muñoz, A., Hernandez, Q., et al. (2000). Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days. Transplantation, 70(7), 989–998.CrossRefPubMedGoogle Scholar
  38. 38.
    Ekser, B., Long, C., Echeverri, G. J., Hara, H., Ezzelarab, M., Lin, C. C., et al. (2010). Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants. American Journal of Transplantation, 10, 273–285.CrossRefPubMedGoogle Scholar
  39. 39.
    Ekser, B., Echeverri, G. J., Hassett, A. C., Yazer, M. H., Long, C., Meyer, M., et al. (2010). Hepatic function after genetically engineered pig liver transplantation in baboons. Transplantation, 90, 483–493.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kim, K., Schuetz, C., Elias, N., Veillette, G. R., Wamala, I., Varma, M., et al. (2012). Up to 9-day survival and control of thrombocytopenia following alpha1,3-galactosyl transferase knockout swine liver xenotransplantation in baboons. Xenotransplantation, 19, 256–264.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Navarro-Alvarez, N., Shah, J. A., Zhu, A., Ligocka, J., Yeh, H., Elias, N., et al. (2016). The effects of exogenous administration of human coagulation factors following pig-to-baboon liver xenotransplantation. American Journal of Transplantation, 16(6), 1715–1725.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Shah, J. A., Navarro-Alvarez, N., DeFazio, M., Rosales, I., Elias, N., Yeh, H., et al. (2016). A bridge to somewhere: 25-day survival following pig-to-baboon liver xenotransplantation. Annals of Surgery, 263(6), 1069–1071.CrossRefPubMedGoogle Scholar
  43. 43.
    Kobayashi, T., Taniguchi, S., Ye, Y., Niekrasz, M., Nour, B., & Cooper, D. K. (1998 Apr). Comparison of bile chemistry between humans, baboons, and pigs: Implications for clinical and experimental liver xenotransplantation. Laboratory Animal Science, 48(2), 197–200.PubMedGoogle Scholar
  44. 44.
    Ekser, B., Lin, C. C., Long, C., Echeverri, G. J., Hara, H., Ezzelarab, M., et al. (2012 Aug). Potential factors influencing the development of thrombocytopenia and consumptive coagulopathy after genetically modified pig liver xenotransplantation. Transplant International, 25(8), 882–896.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Paris, L. L., Chihara, R. K., Sidner, R. A., Joseph Tector, A., & Burlak, C. (2012). Differences in human and porcine platelet oligosaccharides may influence phagocytosis by liver sinusoidal cells in vitro. Xenotransplantation, 19(1), 31–39.CrossRefPubMedGoogle Scholar
  46. 46.
    Peng, Q., Yeh, H., Wei, L., Enjyoj, K., Machaidze, Z., Csizmad, E., et al. (2012). Mechanisms of xenogeneic baboon platelet aggregation and phagocytosis by porcine liver sinusoidal endothelial cells. PloS One, 7(10), 1–7.CrossRefGoogle Scholar
  47. 47.
    Ekser, B., Markmann, J. F., & Tector, A. J. (2015). Current status of pig liver xenotransplantation. International Journal of Surgery, 23, 1–7.CrossRefGoogle Scholar
  48. 48.
    Mohiuddin, M. M., Reichart, B., Byrne, G. W., & McGregor, C. G. A. (2015). Current status of pig heart xenotransplantation. International Journal of Surgery, 23, 234–239.CrossRefPubMedGoogle Scholar
  49. 49.
    Buhler, L., Friedman, T., Iacomini, J., & Cooper, D. K. (1999). Xenotransplantation – state of the art – update 1999. Frontiers in Bioscience, 4(D4), 16–32.Google Scholar
  50. 50.
    Kuwaki, K., Knosalla, C., Dor, F. J. M. F., Gollackner, B., Tseng, Y. L., Houser, S., et al. (2004). Suppression of natural and elicited antibodies in pig-to-baboon heart transplantation using a human anti-human CD154 mAb-based regimen. American Journal of Transplantation, 4(3), 363–372.CrossRefPubMedGoogle Scholar
  51. 51.
    Kuwaki, K., Tseng, Y. L., Dor, F. J., Shimizu, A., Houser, S. L., Lancos, C. J., et al. (2005). Heart transplantation in baboons using alpha1,3-galactosyltransferase gene- knockout pigs as donors: Initial experience. Nature Medicine, 11(1), 29–31.CrossRefPubMedGoogle Scholar
  52. 52.
    Tseng, Y.-L., Kuwaki, K., Dor, F. J. M. F., Shimizu, A., Houser, S., Hisashi, Y., et al. (2005). alpha1,3-galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation, 80(10), 1493–1500.CrossRefPubMedGoogle Scholar
  53. 53.
    Mohiuddin, M. M., Corcoran, P. C., Singh, A. K., Azimzadeh, A., Hoyt, R. F., Thomas, M. L., et al. (2012). B-cell depletion extends the survival of GTKO.hCD46Tg pig heart xenografts in baboons for up to 8 months. American Journal of Transplantation, 12(3), 763–771.CrossRefPubMedGoogle Scholar
  54. 54.
    Mohiuddin, M. M., Singh, A. K., Corcoran, P. C., Hoyt, R. F., Thomas, M. L., Lewis, B. G. T., et al. (2014). 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, 21(1), 35–45.CrossRefPubMedGoogle Scholar
  55. 55.
    Mohiuddin, M. M., Singh, A. K., Corcoran, P. C., Thomas Iii, M. L., Clark, T., Lewis, B. G., et al. (2016). Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nature Communications, 7, 11138.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Iwase, H., Ekser, B., Satyananda, V., Bhama, J., Hara, H., Ezzelarab, M., et al. (2015). Pig-to-baboon heterotopic heart transplantation – exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens. Xenotransplantation, 23, 211–220.CrossRefGoogle Scholar
  57. 57.
    Barnard, C. N., Losman, J. G., Curcio, C. A., Sanchez, H. E., Wolpowitz, A., & Barnard, M. S. (1977). The advantage of heterotopic cardiac transplantation over orthotopic cardiac transplantation in the management of severe acute rejection. The Journal of Thoracic and Cardiovascular Surgery, 74(6), 918–924.PubMedGoogle Scholar
  58. 58.
    Bauer, A., Postrach, J., Thormann, M., Blanck, S., Faber, C., Wintersperger, B., et al. (2010). First experience with heterotopic thoracic pig-to-baboon cardiac xenotransplantation. Xenotransplantation, 17(3), 243–249.CrossRefPubMedGoogle Scholar
  59. 59.
    Mohiuddin, M. M., Singh, A. K., Corcoran, P. C., Hoyt, R. F., Thomas, M. L., Ayares, D., et al. (2014 Sep). Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation. The Journal of Thoracic and Cardiovascular Surgery, 148(3), 1106–1114.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Cooper, D. K., Keogh, A. M., Brink, J., Corris, P. A., Klepetko, W., Pierson, R. N., et al. (2000). 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. The Journal of Heart and Lung Transplantation, 19(12), 1125–1165.CrossRefPubMedGoogle Scholar
  61. 61.
    Byrne, G. W., Du, Z., Sun, Z., Asmann, Y. W., & McGregor, C. G. A. (2011). Changes in cardiac gene expression after pig-to-primate orthotopic xenotransplantation. Xenotransplantation, 18(1), 14–27.CrossRefPubMedGoogle Scholar
  62. 62.
    McGregor, C. G. A., Ricci, D., Miyagi, N., Stalboerger, P. G., Du, Z., Oehler, E. A., et al. (2012). Human CD55 expression blocks hyperacute rejection and restricts complement activation in gal knockout cardiac xenografts. Transplantation, 93(7), 686–692.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Wheeler, D. G., Joseph, M. E., Mahamud, S. D., Aurand, W. L., Mohler, P. J., Pompili, V. J., et al. (2012). Transgenic swine: Expression of human CD39 protects against myocardial injury. Journal of Molecular and Cellular Cardiology, 52(5), 958–961.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    den Hengst, W. A., Gielis, J. F., Lin, J. Y., Van Schil, P. E., De Windt, L. J., & Moens, A. L. (2010). Lung ischemia-reperfusion injury: A molecular and clinical view on a complex pathophysiological process. American Journal of Physiology, Heart and Circulatory Physiology, 299(5), H1283–H1299.CrossRefGoogle Scholar
  65. 65.
    Ranieri, V., Suter, P., Tortorella, C., De Tullio, R., Dayer, J., Brienza, A., et al. (1999). Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial. Journal of the American Medical Association, 282(1), 54–61.CrossRefPubMedGoogle Scholar
  66. 66.
    Pierson, R. N. (2009). Antibody-mediated xenograft injury: Mechanisms and protective strategies. Transplant Immunology, 21(2), 65–69.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Nguyen, B. N. H., Azimzadeh, A. M., Zhang, T., Wu, G., Shuurman, H. J., Sachs, D. H., et al. (2007). Life-supporting function of genetically modified swine lungs in baboons. The Journal of Thoracic and Cardiovascular Surgery, 133(5), 1354–1363.CrossRefPubMedGoogle Scholar
  68. 68.
    Kubicki, N., Laird, C., Burdorf, L., Pierson, R. N., & Azimzadeh, A. M. (2015). Current status of pig lung xenotransplantation. International Journal of Surgery, 23, 247–254.CrossRefPubMedGoogle Scholar
  69. 69.
    Burdorf, L., Azimzadeh, A. M., & Pierson, R. N. (2012). Xenogeneic lung transplantation models. Methods in Molecular Biology, 885(4), 169–189.CrossRefPubMedGoogle Scholar
  70. 70.
    Sanchez, P. G., Bittle, G. J., Burdorf, L., Pierson, R. N., & Griffith, B. P. (2012). State of art: Clinical ex vivo lung perfusion: Rationale, current status, and future directions. The Journal of Heart and Lung Transplantation, 31(4), 339–348.CrossRefPubMedGoogle Scholar
  71. 71.
    Harris, D. G., Quinn, K. J., French, B. M., Schwartz, E., Kang, E., Dahi, S., et al. (2015). Meta-analysis of the independent and cumulative effects of multiple genetic modifications on pig lung xenograft performance during ex vivo perfusion with human blood. Xenotransplantation, 22(2), 102–111.CrossRefPubMedGoogle Scholar
  72. 72.
    Collins, B. J., Blum, M. G., Parker, R. E., Chang, A. C., Blair, K. S., Zorn, G. L., et al. (2001). Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection. Journal of Applied Physiology, 90(6), 2257–2268.CrossRefPubMedGoogle Scholar
  73. 73.
    Cooper, D. K. C., Ekser, B., Burlak, C., Ezzelarab, M., Hara, H., Paris, L., et al. (2013). Clinical lung xenotransplantation – what donor genetic modifications may be necessary? Xenotransplantation, 19(3), 144–158.CrossRefGoogle Scholar
  74. 74.
    Kim, Y. T., Lee, H. J., Lee, S. W., Kim, J. Y., Wi, H. C., Park, S. J., et al. (2008). Pre-treatment of porcine pulmonary xenograft with desmopressin: A novel strategy to attenuate platelet activation and systemic intravascular coagulation in an ex-vivo model of swine-to-human pulmonary xenotransplantation. Xenotransplantation, 15(1), 27–35.CrossRefPubMedGoogle Scholar
  75. 75.
    Chen, D., Riesbeck, K., McVey, J. H., Kemball-Cook, G., Tuddenham, E. G., Lechler, R. I., et al. (1999). Regulated inhibition of coagulation by porcine endothelial cells expressing P-selectin-tagged hirudin and tissue factor pathway inhibitor fusion proteins. Transplantation, 68(6), 832–839.CrossRefPubMedGoogle Scholar
  76. 76.
    Shapiro, A. M., Lakey, J. R., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., et al. (2000 Jul 27). Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. The New England Journal of Medicine, 343(4), 230–238.CrossRefPubMedGoogle Scholar
  77. 77.
    Bottino, R., Balamurugan, A. N., Smetanka, C., Bertera, S., He, J., Rood, P. P. M., et al. (2007). Isolation outcome and functional characteristics of young and adult pig pancreatic islets for transplantation studies. Xenotransplantation, 14(1), 74–82.CrossRefPubMedGoogle Scholar
  78. 78.
    Eventov-Friedman, S., Tchorsh, D., Katchman, H., Shezen, E., Aronovich, A., Hecht, G., et al. (2006). Embryonic pig pancreatic tissue transplantation for the treatment of diabetes. PLoS Medicine, 3(7), 1165–1177.CrossRefGoogle Scholar
  79. 79.
    Hering, B. J., Wijkstrom, M., Graham, M. L., Hårdstedt, M., Aasheim, T. C., Jie, T., et al. (2006). Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nature Medicine, 12(3), 301–303.CrossRefPubMedGoogle Scholar
  80. 80.
    Cardona, K., Korbutt, G. S., Milas, Z., Lyon, J., Cano, J., Jiang, W., et al. (2006). Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nature Medicine, 12(3), 304–306.CrossRefPubMedGoogle Scholar
  81. 81.
    Van Der Windt, D. J., Bottino, R., Casu, A., Campanile, N., Smetanka, C., He, J., et al. (2009). Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. American Journal of Transplantation, 9(12), 2716–2726.CrossRefPubMedGoogle Scholar
  82. 82.
    Thompson, P., Badell, I. R., Lowe, M., Cano, J., Song, M., Leopardi, F., et al. (2011 Dec). Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. American Journal of Transplantation, 11(12), 2593–2602.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Park, C. G., Bottino, R., & Hawthorne, W. J. (2015). Current status of islet xenotransplantation. International Journal of Surgery, 23, 261–266.CrossRefPubMedGoogle Scholar
  84. 84.
    Hawthorne, W. J., Salvaris, E. J., Phillips, P., Hawkes, J., Liuwantara, D., Burns, H., et al. (2014). Control of IBMIR in neonatal porcine islet xenotransplantation in baboons. American Journal of Transplantation, 14(6), 1300–1309.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Thompson, P., Cardona, K., Russell, M., Badell, I. R., Shaffer, V., Korbutt, G., et al. (2011). CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. American Journal of Transplantation, 11(5), 947–957.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Dufrane, D., Goebbels, R.-M., & Gianello, P. (2010). Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation, 90(10), 1054–1062.CrossRefPubMedGoogle Scholar
  87. 87.
    Estrada, J. L., Martens, G., Li, P., Adams, A., Newell, K. A., Ford, M. L., et al. (2015). Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/β4GalNT2 genes. Xenotransplantation, 22(3), 194–202.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Cooper, D. K., Ekser, B., Ramsoondar, J., et al. (2016). The role of genetically engineered pigs in xenotransplantation. The Journal of Pathology, 238(2), 288–299.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical SchoolBostonUSA
  2. 2.Transplant Division, Department of SurgeryIndiana University School of MedicineIndianapolisUSA

Personalised recommendations

Cite chapter