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  • Review Article
  • Published:

Xenotransplantation: current status and a perspective on the future

Nature Reviews Immunology volume 7, pages 519–531 (2007)Cite this article

Key Points

  • The severe shortage of human organ donors limits the practice of clinical transplantation, the only effective therapy for end-stage organ failure. Xenotransplantation using pig organs might provide the most immediate solution to the scarcity of human organ donors.

  • Immunological rejection of xenografts presents the most formidable obstacle to clinical xenotransplantation. Both innate and adaptive immune systems contribute to xenograft rejection.

  • The availability of α1,3-galactosyltransferase-deficient pigs and pigs transgenic for human complement regulatory proteins have made it possible to overcome hyperacute rejection. However, with these pigs it has not been possible to completely prevent acute humoral xenograft rejection unless a tolerance-inducing protocol is used.

  • Innate immune cells mediate much stronger responses to xenografts than to allografts. Genetic modifications of pigs to remove xenoantigens that interact with the activating receptors of human natural killer (NK) cells and macrophages, and to provide the ligands that interact with the inhibitory receptors of these cells may confer protection against cytotoxicity by NK cells and macrophages.

  • Nonspecific immunosuppression has been insufficient to prevent porcine xenograft rejection in non-human primates without severe toxicity. Tolerance induction is probably required to overcome the delayed form of humoral rejection and T-cell xenoresponses.

  • The observation of porcine endogenous retroviruses (PERVs) infecting human cells in vitro has raised concerns regarding the safety of xenotransplantation. However, studies so far have provided no evidence of xenotransplantation-associated PERV transmission to humans in vivo. The risk for xenotransplantation-mediated zoonosis will never be completely eliminated, and constant vigilance will be required as clinical xenotransplantation proceeds.

  • Worldwide harmonization of regulatory guidelines for oversight is needed to address the infectious risks associated with clinical xenotransplantation. In contrast to allotransplantation, both the patients and the public must be included when considering the benefit versus risk of xenotransplantation.

Abstract

Xenotransplantation using pigs as the transplant source has the potential to resolve the severe shortage of human organ donors. Although the development of relatively non-toxic immunosuppressive or tolerance-inducing regimens will be required to justify clinical trials using pig organs, recent advances in our understanding of the biology of xenograft rejection and zoonotic infections, and the generation of α1,3-galactosyltransferase-deficient pigs have moved this approach closer to clinical application. This Review highlights the major obstacles impeding the translation of xenotransplantation into clinical therapies and the potential solutions, providing a perspective on the future of clinical xenotransplantation.

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Figure 1: Humoral rejection.
Figure 2: Cellular rejection.
Figure 3: Induction of B-cell tolerance.

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References

  1. Cooper, D. K. C., Gollackner, B. & Sachs, D. H. Will the pig solve the transplantation backlog? Annu. Rev. Med. 53, 133–147 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Groth, C. G. et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 344, 1402–1404 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Elliott, R. B. et al. Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation 14, 157–161 (2007).

    Article  PubMed  Google Scholar 

  4. Cardona, K. et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nature Med. 12, 304–306 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Hering, B. J. et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nature Med. 12, 301–303 (2006). References 4 and 5 show that chronic immunosuppressive protocols based on co-stimulatory blockade allow long-term porcine pancreatic-islet xenograft survival and diabetes reversal in non-human primate recipients. Such immunosuppresive protocols are not yet justified in the clinic because of their complications.

    Article  CAS  PubMed  Google Scholar 

  6. Galili, U. Interaction of the natural anti-Gal antibody with α-galactosyl epitopes: a major obstacle for xenotransplantation in humans. Immunol. Today 14, 480–482 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Schuurman, H. J., Cheng, J. & Lam, T. Pathology of xenograft rejection: a commentary. Xenotransplantation 10, 293–299 (2003).

    Article  PubMed  Google Scholar 

  8. Shimizu, I., Smith, N. R., Zhao, G., Medof, E. & Sykes, M. Decay-accelerating factor prevents acute humoral rejection induced by low levels of anti-αGal natural antibodies. Transplantation 81, 95–100 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Davila, E. et al. T-cell responses during pig-to-primate xenotransplantation. Xenotransplantation 13, 31–40 (2006).

    Article  PubMed  Google Scholar 

  10. Ramirez, P. et al. Prevention of hyperacute rejection in a model of orthotopic liver xenotransplantation from pig to baboon using polytransgenic pig livers (CD55, CD59, and H-Transferase). Transplantation Proc. 37, 4103–4106 (2005).

    Article  CAS  Google Scholar 

  11. Gollackner, B. et al. Acute vascular rejection of xenografts: roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activity. Transplantation 77, 1735–1741 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Shimizu, A. et al. Thrombotic microangiopathic glomerulopathy in human decay accelerating factor-transgenic swine-to-baboon kidney xenografts. J. Am. Soc. Nephrol. 16, 2732–2745 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Yamada, K. et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of α1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nature Med. 11, 32–34 (2005). This paper shows that combined kidney and vascularized thymus transplants from α1,3GalT-deficient pigs led to long-term (up to 83 days) xenograft survival; the renal grafts remained functional without evidence of rejection until the time of death, which was unrelated to the transplantation.

    Article  CAS  PubMed  Google Scholar 

  14. Crikis, S., Cowan, P. J. & D'Apice, A. J. Intravascular thrombosis in discordant xenotransplantation. Transplantation 82, 1119–1123 (2006).

    Article  PubMed  Google Scholar 

  15. Schulte am, E. J., Rogiers, X. & Robson, S. C. Molecular incompatibilities in hemostasis between swine and men—impact on xenografting. Ann. Transplant. 6, 12–16 (2001).

    Google Scholar 

  16. Goto, M., Groth, C. G., Nilsson, B. & Korsgren, O. Intraportal pig islet xenotransplantation into athymic mice as an in vivo model for the study of the instant blood-mediated inflammatory reaction. Xenotransplantation 11, 195–202 (2004).

    Article  PubMed  Google Scholar 

  17. Keusch, J. J., Manzella, S. M., Nyame, K. A., Cummings, R. D. & Baenziger, J. U. Expression cloning of a new member of the ABO blood group glycosyltransferases, iGb3 synthase, that directs the synthesis of isoglobo-glycosphingolipids. J. Biol. Chem. 275, 25308–25314 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Milland, J. et al. The molecular basis for Galα(1,3)Gal expression in animals with a deletion of the α1,3galactosyltransferase gene. J. Immunol. 176, 2448–2454 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Sharma, A. et al. Pig cells that lack the gene for α1–3 galactosyltransferase express low levels of the gal antigen. Transplantation 75, 430–436 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Kuwaki, K. et al. Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nature Med. 11, 29–31 (2005). This paper shows that α1,3GalT-deficient pig heart xenografts survived for 2–6 months in baboons that had received an immunosuppressive regimen based on CD40L-specific antibodies. However, tolerance was not achieved and the recipients eventually rejected the grafts.

    Article  CAS  PubMed  Google Scholar 

  21. Zhou, D. et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–1789 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Dorling, A., Lombardi, G., Binns, R. & Lechler, R. I. Detection of primary direct and indirect human anti-porcine T cell responses using a porcine dendritic cell population. Eur. J. Immunol. 26, 1378–1387 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. McGregor, C. G. A. et al. Cardiac xenotransplantation: recent preclinical progress with 3-month median survival. J. Thorac. Cardiovasc. Surg. 130, 844–851 (2005).

    Article  PubMed  Google Scholar 

  24. Sachs, D. H. A knock-out punch? Nature Med. 11, 1271 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Seebach, J. D. et al. HLA-Cw3 expression on porcine endothelial cells protects against xenogeneic cytotoxicity mediated by a subset of human NK cells. J. Immunol. 159, 3655–3661 (1997). This paper shows that the expression of HLA class I on porcine cells inhibits their killing by human NK cells.

    CAS  PubMed  Google Scholar 

  26. Sharland, A. et al. Genetically modified HLA class I molecules able to inhibit human NK cells without provoking alloreactive CD8+ CTLs. J. Immunol. 168, 3266–3274 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Ito, M. et al. Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J. Exp. Med. 203, 289–295 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Moretta, A., Biassoni, R., Bottino, C., Mingari, M. C. & Moretta, L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol. Today 21, 228–234 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Nakamura, M. C. et al. Natural killing of xenogeneic cells mediated by the mouse Ly-49D receptor. J. Immunol. 163, 4694–4700 (1999).

    CAS  PubMed  Google Scholar 

  30. Forte, P., Lilienfeld, B. G., Baumann, B. C. & Seebach, J. D. Human NK cytotoxicity against porcine cells is triggered by NKp44 and NKG2D. J. Immunol. 175, 5463–5470 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Lilienfeld, B. G., Garcia-Borges, C., Crew, M. D. & Seebach, J. D. Porcine UL16-binding protein 1 expressed on the surface of endothelial cells triggers human NK cytotoxicity through NKG2D. J. Immunol. 177, 2146–2152 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Christiansen, D. et al. Recognition of a carbohydrate xenoepitope by human NKRP1A (CD161). Xenotransplantation 13, 440–446 (2006).

    Article  PubMed  Google Scholar 

  33. Nikolic, B., Cooke, D. T., Zhao, G. & Sykes, M. Both γδ T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells and the induction of xenograft tolerance in mice. J. Immunol. 166, 1398–1404 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Goodman, D. J., Millan, M. T., Ferran, C. & Bach, F. H. in Xenotransplantation: The Transplantation of Organs and Tissues Between Species (eds Cooper, D. K. C., Kemp, E., Platt, J. L. & White, D. J. G.) 77–94 (Springer, Heidelberg, 1997).

    Book  Google Scholar 

  35. Gourlay, W. A., Chambers, W. H., Monaco, A. P. & Maki, T. Importance of natural killer cells in the rejection of hamster skin xenografts. Transplantation 65, 727–734 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Abe, M. et al. Elimination of porcine hemopoietic cells by macrophages in mice. J. Immunol. 168, 621–628 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Basker, M. et al. Clearance of mobilized porcine peripheral blood progenitor cells is delayed by depletion of the phagocytic reticuloendothelial system in baboons. Transplantation 72, 1278–1285 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Ide, K. et al. Antibody- and complement-independent phagocytotic and cytolytic activities of human macrophages toward porcine cells. Xenotransplantation 12, 181–188 (2005).

    Article  PubMed  Google Scholar 

  39. Candinas, D. et al. T cell independence of macrophage and natural killer cell infiltration, cytokine production, and endothelial activation during delayed xenograft rejection. Transplantation 62, 1920–1927 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Burlak, C., Twining, L. M. & Rees, M. A. Terminal sialic acid residues on human glycophorin A are recognized by porcine Kupffer cells. Transplantation 80, 344–352 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Jin, R., Greenwald, A., Peterson, M. D. & Waddell, T. K. Human monocytes recognize porcine endothelium via the interaction of galectin 3 and α-GAL. J. Immunol. 177, 1289–1295 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, H. et al. Attenuation of phagocytosis of xenogeneic cells by manipulating CD47. Blood 109, 836–842 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ide, K. et al. Role for CD47–SIRPα signaling in xenograft rejection by macrophages. Proc. Natl Acad. Sci. USA 104, 5062–5066 (2007). References 42 and 43 provide evidence that the lack of functional interaction between donor CD47 and recipient SIRPα contributes significantly to phagocytosis of porcine cells by xenogeneic macrophages, suggesting that CD47 may provide a useful molecular target for preventing xenograft rejection by macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yi, S. et al. T cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts. J. Immunol. 170, 2750–2758 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Oldenborg, P. A. et al. Role of CD47 as a marker of self on red blood cells. Science 288, 2051–2054 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Al Mohanna, F. et al. Activation of naive xenogeneic but not allogeneic endothelial cells by human naive neutrophils: a potential occult barrier to xenotransplantation. Am. J. Pathol. 151, 111–120 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Al Mohanna, F., Saleh, S., Parhar, R. S., Khabar, K. & Collison, K. Human neutrophil gene expression profiling following xenogeneic encounter with porcine aortic endothelial cells: the occult role of neutrophils in xenograft rejection revealed. J. Leukoc. Biol. 78, 51–61 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Nicolas, J. M. & Fishman, J. A. Infectious risk in xenotransplantation. Curr. Opin. Organ Transplant. 11, 180–184 (2006).

    Article  Google Scholar 

  49. Oldmixon, B. A. et al. Porcine endogenous retrovirus transmission characteristics of an inbred herd of miniature swine. J. Virol. 76, 3045–3048 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Clemenceau, B., Jegou, D., Martignat, L. & Sai, P. Microchimerism and transmission of porcine endogenous retrovirus from a pig cell line or specific pathogen-free pig islets to mouse tissues and human cells during xenografts in nude mice. Diabetologia 45, 914–923 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Yang, Y. G. et al. Mouse retrovirus mediates porcine endogenous retrovirus transmission into human cells in long-term human-porcine chimeric mice. J. Clin. Invest. 114, 695–700 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Oldmixon, B. A. et al. Porcine endogenous retrovirus transmission characteristics of an inbred herd of miniature swine. J. Virol. 76, 3045–3048 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Garkavenko, O. et al. Monitoring for potentially xenozoonotic viruses in New Zealand pigs. J. Med. Virol. 72, 338–344 (2004).

    Article  PubMed  Google Scholar 

  54. Dwyer, K. M., Cowan, P. J. & d'Apice, A. J. F. Xenotransplantation: past achievements and future promise. Heart Lung Circ. 11, 32–41 (2002).

    Article  PubMed  Google Scholar 

  55. Lin, Y. et al. Long-term survival of hamster hearts in presensitized rats. J. Immunol. 164, 4883–4892 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Tabata, T. et al. Accommodation after lung xenografting from hamster to rat. Transplantation 75, 607–612 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Koch, C. A., Khalpey, Z. I. & Platt, J. L. Accommodation: preventing injury in transplantation and disease. J. Immunol. 172, 5143–5148 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Lin, S. S. et al. The role of anti-Galα1–3Gal antibodies in acute vascular rejection and accommodation of xenografts. Transplantation 70, 1667–1674 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Cowan, P. J. et al. Protective effects of recombinant human antithrombin III in pig-to-primate renal xenotransplantation. Am. J. Transplant. 2, 520–525 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Byrne, G. W. et al. Warfarin or low-molecular-weight heparin therapy does not prolong pig-to-primate cardiac xenograft function. Am. J. Transplant. 5, 1011–1020 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Cozzi, E. et al. Effects of long-term administration of high-dose recombinant human antithrombin in immunosuppressed primate recipients of porcine xenografts. Transplantation 80, 1501–1510 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Imai, M. et al. Modulation of nucleoside triphosphate diphosphohydrolase-1 (NTPDase-1)cd39 in xenograft rejection. Mol. Med. 5, 743–752 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Enjyoji, K. et al. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nature Med. 5, 1010–1017 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Imai, M. et al. Recombinant adenoviral mediated CD39 gene transfer prolongs cardiac xenograft survival. Transplantation 70, 864–870 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Dwyer, K. M. et al. Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation. J. Clin. Invest. 113, 1440–1446 (2004). References 63–65 indicate the potential of overexpression of CD39 in the graft to prevent the thrombosis associated with graft loss.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen, D. et al. Complete inhibition of acute humoral rejection using regulated expression of membrane-tethered anticoagulants on xenograft endothelium. Am. J. Transplant. 4, 1958–1963 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Sandrin, M. S. et al. Enzymatic remodelling of the carbohydrate surface of a xenogeneic cell substantially reduces human antibody binding and complement-mediated cytolysis. Nature Med. 1, 1261–1267 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Sharma, A. et al. Reduction in the level of Galα(1,3)Gal in transgenic mice and pigs by the expression of an α(1,2)fucosyltransferase. Proc. Natl Acad. Sci. USA 93, 7190–7195 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McKenzie, I. F., Li, Y. Q., Patton, K. & Sandrin, M. S. Fucosyl transferase (H) transgenic heart transplants to Gal−/− mice. Transplantation 70, 1205–1209 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Lai, L. et al. Production of α-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 295, 1089–1092 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Dai, Y. et al. Targeted disruption of the α1,3-galactosyltransferase gene in cloned pigs. Nature Biotechnol. 20, 251–255 (2002). References 70 and 71 demonstrate the feasibility of producing α1,3GalT-deficient pigs.

    Article  CAS  Google Scholar 

  72. Kolber-Simonds, D. et al. Production of α-1,3-galactosyltransferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations. Proc. Natl Acad. Sci. USA 101, 7335–7340 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen, G. et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys. Nature Med. 11, 1295–1298 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Yang, Y. G. et al. Tolerization of anti-Galα1–3Gal natural antibody-forming B cells by induction of mixed chimerism. J. Exp. Med. 187, 1335–1342 (1998). This study provides the first evidence that mixed haematopoietic chimerism can induce tolerance of α1,3Gal-specific natural-antibody-producing B cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ohdan, H., Yang, Y. G., Shimizu, A., Swenson, K. G. & Sykes, M. Mixed chimerism induced without lethal conditioning prevents T cell- and anti-Galα1,3Gal-mediated graft rejection. J. Clin. Invest. 104, 281–290 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ohdan, H., Yang, Y. G., Swenson, K. G., Kitamura, H. & Sykes, M. T cell and B cell tolerance to GALα1,3GAL-expressing heart xenografts is achieved in α1,3-galactosyltransferase-deficient mice by nonmyeloablative induction of mixed chimerism. Transplantation 71, 1532–1542 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Kawahara, T., Shimizu, I., Ohdan, H., Zhao, G. & Sykes, M. Differing mechanisms of early and late B cell hyporesponsiveness induced by mixed chimerism. Am. J. Transplant. 5, 2821–2829 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Shimizu, I. et al. B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-αGal-producing B-1 cells. Blood 109, 1773–1781 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Aksentijevich, I., Sachs, D. H. & Sykes, M. Humoral tolerance in xenogeneic BMT recipients conditioned with a non-myeloablative regimen. Transplantation 53, 1108–1114 (1992).

    Article  CAS  PubMed  Google Scholar 

  80. Bracy, J. L., Sachs, D. H. & Iacomini, J. Inhibition of xenoreactive natural antibody production by retroviral gene therapy. Science 281, 1845–1847 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Mitsuhashi, N. et al. Tolerance induction by lentiviral gene therapy with a nonmyeloablative regimen. Blood 107, 2286–2293 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Hancock, W. W. et al. Effects of leflunomide and deoxyspergualin in the guinea pig→rat cardiac model of delayed xenograft rejection: suppression of B cell and C-C chemokine responses but not induction of macrophage lectin. Transplantation 64, 696–704 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Lin, Y., Goebels, J., Xia, G., Vandeputte, M. & Waer, M. Induction of specific transplantation tolerance across xenogeneic barriers in the T-independent immune compartment. Nature Med. 4, 173–180 (1998). This study shows the effectiveness of leflunomide in inducing T-cell-independent B-cell tolerance.

    Article  CAS  PubMed  Google Scholar 

  84. Yin, D. et al. Induction of species-specific host accommodation in the hamster-to-rat xenotransplantation model. J. Immunol. 161, 2044–2051 (1998).

    CAS  PubMed  Google Scholar 

  85. Yan, Y. et al. Effects of a short course of leflunomide on T-independent B-lymphocyte xenoreactivity and on susceptibility of xenografts to acute or chronic rejection. Transplantation 79, 135–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Fan, X. et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nature Med. 10, 1227–1233 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Stussi, G., West, L., Cooper, D. K. C. & Seebach, J. D. ABO-incompatible allotransplantation as a basis for clinical xenotransplantation. Xenotransplantation 13, 390–399 (2006).

    Article  PubMed  Google Scholar 

  88. Kuwaki, K. et al. Suppression of natural and elicited antibodies in pig-to-baboon heart transplantation using a human anti-human CD154 mAb-based regimen. Am. J. Transplant. 4, 363–372 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Teotia, S. S. et al. Prevention, detection, and management of early bacterial and fungal infections in a preclinical cardiac xenotransplantation model that achieves prolonged survival. Xenotransplantation 12, 127–133 (2005).

    Article  PubMed  Google Scholar 

  90. Dufrane, D., Goebbels, R. M., Saliez, A., Guiot, Y. & Gianello, P. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation 81, 1345–1353 (2006).

    Article  PubMed  Google Scholar 

  91. Kizilel, S., Garfinkel, M. & Opara, E. The bioartificial pancreas: progress and challenges. Diabetes Technol. Ther. 7, 968–985 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Valdés-González, R. A. et al. Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. Eur. J. Endocrinol. 153, 419–427 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Salazar, A. & Wright, J. R. Jr. Islet xenotransplantation clinical trial: does histology show islet cells? Eur. J. Endocrinol. 154, 917–918 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Sykes, M. & Cozzi, E. Xenotransplantation of pig islets into Mexican children: were the fundamental ethical requirements to proceed with such a study really met? Eur. J. Endocrinol. 154, 921–922 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Lenschow, D. J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 257, 789–792 (1992).

    Article  CAS  PubMed  Google Scholar 

  96. Gordon, E. J. et al. Rat xenograft survival in mice treated with donor-specific transfusion and anti-CD154 antibody is enhanced by elimination of host CD4+ cells. Transplantation 71, 319–327 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Chen, W. et al. Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells. J. Immunol. 175, 3409–3416 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Lee, L. A. et al. Specific tolerance across a discordant xenogeneic transplantation barrier. Proc. Natl Acad. Sci. USA 91, 10864–10867 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhao, Y., Swenson, K., Sergio, J. J. & Sykes, M. Pig MHC mediates positive selection of mouse CD4+ T cells with a mouse MHC-restricted TCR in pig thymus grafts. J. Immunol. 161, 1320–1326 (1998).

    CAS  PubMed  Google Scholar 

  100. Zhao, Y. et al. Positive and negative selection of functional mouse CD4 cells by porcine MHC in pig thymus grafts. J. Immunol. 159, 2100–2109 (1997).

    CAS  PubMed  Google Scholar 

  101. Zhao, Y., Rodriguez-Barbosa, J. I., Shimizu, A., Sachs, D. H. & Sykes, M. Despite efficient intrathymic negative selection of host-reactive T cells, autoimmune disease may develop in porcine thymus-grafted athymic mice: evidence for failure of regulatory mechanisms suppressing autoimmunity. Transplantation 75, 1832–1840 (2003).

    Article  PubMed  Google Scholar 

  102. Zhao, Y. et al. Skin graft tolerance across a discordant xenogeneic barrier. Nature Med. 2, 1211–1216 (1996). This study demonstrates the ability of thymic transplantation to induce xenograft tolerance.

    Article  CAS  PubMed  Google Scholar 

  103. Zhao, Y. et al. Immune restoration by fetal pig thymus grafts in T cell-depleted, thymectomized mice. J. Immunol. 158, 1641–1649 (1997).

    CAS  PubMed  Google Scholar 

  104. Xia, G., Goebels, J., Rutgeerts, O., Vandeputte, M. & Waer, M. Transplantation tolerance and autoimmunity after xenogeneic thymus transplantation. J. Immunol. 166, 1843–1854 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Yan, Y. et al. Pathogenesis of autoimmunity after xenogeneic thymus transplantation. J. Immunol. 170, 5936–5946 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Nikolic, B. et al. Normal development in porcine thymus grafts and specific tolerance of human T cells to porcine donor MHC. J. Immunol. 162, 3402–3407 (1999).

    CAS  PubMed  Google Scholar 

  107. Wu, A. et al. Xenogeneic thymus transplantation in a pig-to-baboon model. Transplantation 75, 282–291 (2003).

    Article  PubMed  Google Scholar 

  108. Barth, R. N. et al. Xenogeneic thymokidney and thymic tissue transplantation in a pig-to-baboon model: I. Evidence for pig-specific T-cell unresponsiveness. Transplantation 75, 1615–1624 (2003).

    Article  PubMed  Google Scholar 

  109. Yamamoto, S. et al. Vascularized thymic lobe transplantation in a pig-to-baboon model: a novel strategy for xenogeneic tolerance induction and T-cell reconstitution. Transplantation 80, 1783–1790 (2005).

    Article  PubMed  Google Scholar 

  110. Sykes, M. Mixed chimerism and transplant tolerance. Immunity 14, 417–424 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Cosimi, A. B. & Sachs, D. H. Mixed chimerism and transplantation tolerance. Transplantation 77, 943–946 (2004).

    Article  PubMed  Google Scholar 

  112. Abe, M., Qi, J., Sykes, M. & Yang, Y. G. Mixed chimerism induces donor-specific T cell tolerance across a highly disparate xenogeneic barrier. Blood 99, 3823–3829 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Chen, A. M. et al. Porcine stem cell engraftment and seeding of murine thymus with class II+ cells in mice expressing porcine cytokines: toward tolerance induction across discordant xenogeneic barriers. Transplantation 69, 2484–2490 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Lan, P. et al. Induction of human T cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism. Blood 103, 3964–3969 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Lan, P., Tonomura, N., Shimizu, A., Wang, S. & Yang, Y. G. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 108, 487–492 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Ito, H., Takeuchi, Y., Shaffer, J. & Sykes, M. Anti-CD40L monoclonal antibodies can replace anti-CD4 monoclonal antibodies for the nonmyeloablative induction of mixed xenogeneic chimerism. Transplantation 82, 251–257 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Fudaba, Y. et al. Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: In vivo and in vitro analyses. Am. J. Transplant. 6, 2121–2133 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Murakami, M. et al. Long-term xurvival of xenogeneic heart grafts achieved by costimulatory blockade and transient mixed chimerism. Transplantation 82, 275–281 (2006).

    Article  PubMed  Google Scholar 

  119. US Department of Health and Human Services Secretary's Advisory Committee on Xenotransplantation (SACX). Informed consent in clinical resarch involving xenotransplantation. [online] (2004).

  120. Sykes, M., d'Apice, A. & Sandrin, M. Position paper of the ethics committee of the international xenotransplantation association. Xenotransplantation 10, 194–203 (2003).

    Article  PubMed  Google Scholar 

  121. Sykes, M. Commentary: World Health Assembly resolution 57.18 on xenotransplantation. Transplantation 79, 636–637 (2005).

    Article  PubMed  Google Scholar 

  122. Tomita, Y., Khan, A. & Sykes, M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantion in mice conditioned with a non-myeloablative regimen. J. Immunol. 153, 1087–1098 (1994).

    CAS  PubMed  Google Scholar 

  123. Khan, A., Tomita, Y. & Sykes, M. Thymic dependence of loss of tolerance in mixed allogeneic bone marrow chimeras after depletion of donor antigen. Transplantation 62, 380–387 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Ehl, S. et al. Viral and bacterial infections interfere with peripheral tolerance induction and activate CD8+T cells to cause immunopathology. J. Exp. Med. 187, 763–774 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Rossini, A. A., Mordes, J. P., Greiner, D. L. & Stoff, J. S. Islet cell transplantation tolerance. Transplantation 72, S43–S46 (2001).

    CAS  PubMed  Google Scholar 

  126. Tseng, Y. L. et al. Bone marrow transplantation from α1,3-galactosyltransferase gene-knockout pigs in baboons. Xenotransplantation 11, 361–370 (2004).

    Article  PubMed  Google Scholar 

  127. Zhao, Y., Ohdan, H., Manilay, J. O. & Sykes, M. NK cell tolerance in mixed allogeneic chimeras. J. Immunol. 170, 5398–5405 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Chari, R. S. et al. Treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation. N. Engl. J. Med. 331, 234–237 (1994).

    Article  CAS  PubMed  Google Scholar 

  129. Makowka, L. et al. The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure. Transplantation 59, 1654–1659 (1995).

    Article  Google Scholar 

  130. Nagata, H. et al. Prolonged survival of porcine hepatocytes in cynomolgus monkeys. Gastroenterology 132, 321–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Boehmer, J. P. & Popjes, E. Cardiac failure: mechanical support strategies. Crit. Care Med. 34, S268–S277 (2006).

    Article  PubMed  Google Scholar 

  132. Lietz, K. & Miller, L. W. Will left-ventricular assist device therapy replace heart transplantation in the foreseeable future? Curr. Opin. Cardiol. 20, 132–137 (2005).

    PubMed  Google Scholar 

  133. Mehta, S. M., Silber, D., Boehmer, J. P., Christensen, D. & Pae, W. E. Jr. Report of the first U. S. patient successfully supported long term with the LionHeart completely implantable left ventricular assist device system. ASAIO J. 52, e31–e32 (2006).

    Article  PubMed  Google Scholar 

  134. Fissell, W. H. Developments towards an artificial kidney. Expert Rev. Med. Devices 3, 155–165 (2006).

    Article  PubMed  Google Scholar 

  135. Humes, H. D. et al. Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure. Kidney Int. 66, 1578–1588 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Janssens, S. et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367, 113–121 (2006).

    Article  PubMed  Google Scholar 

  137. Zohlnhofer, D. et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 295, 1003–1010 (2006).

    Article  PubMed  Google Scholar 

  138. Bishop, A. E. & Rippon, H. J. Stem cells — potential for repairing damaged lungs and growing human lungs for transplant. Expert Opin. Biol. Ther. 6, 751–758 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Anversa, P., Leri, A. & Kajstura, J. Cardiac regeneration. J. Am. Coll. Cardiol. 47, 1769–1776 (2006).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank A. Dorling and J.A. Fishman for critical reading of the manuscript, and K. Walsh for expert assistance with the manuscript. We apologize to those investigators whose work could not be cited as a result of space limitations. Y.-G.Y. is supported by grants from the Juvenile Diabetes Research Foundation (JDRF), the National Institutes of Health (NIH), USA, the Roche Organ Transplantation Research Foundation and the American Cancer Society. M.S. is supported by grants from the NIH, the Multiple Myeloma Foundation and the JDRF.

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  1. Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, 02129, Massachusetts, USA

    Yong-Guang Yang & Megan Sykes

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  1. Yong-Guang Yang
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Correspondence to Megan Sykes.

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Glossary

Hyperacute rejection

(HAR). A type of humoral rejection that occurs within minutes to hours after transplantation of a porcine vascularized organ in primates. HAR is mediated mainly by natural antibodies directed against Galα1–3Galβ1–4GlcNAc, and is characterized histologically by diffuse interstitial haemorrhage, oedema and thrombosis of small vessels.

Acute humoral xenograft rejection

(AHXR). A form of injury that develops several days to weeks after transplantation of a vascularized xenograft. AHXR can be induced by low levels of natural and elicited antibodies.

Porcine endogenous retroviruses

(PERVs). Retroviral sequences in the pig genome that are inherited through infection of pig germ cells.

Natural antibodies

Antibodies found in individuals that have not had any previous known exposure to the antigen recognized by the antibodies.

Thrombotic microangiopathy

Vascular lesions characterized by aggregation of platelets and thrombosis in small vessels and capillaries.

Disseminated intravascular coagulation

(DIC). Systemic intravascular coagulation and thrombosis, which is associated with haemorrhage owing to the consumption of pro-coagulants and platelets.

Natural killer T cells

(NKT cells). A subpopulation of T cells that expresses both NK-cell and T-cell markers. In the C57BL/6 mouse strain, NKT cells express the NK1.1 (NKRP1C) molecule and the αβ-T-cell receptor (TCR). Some NKT cells recognize CD1d-associated lipid antigens and express a restricted repertoire of TCRs.

Antibody-dependent cell-mediated cytotoxicity

A cytotoxic mechanism by which an antibody-coated target cell is directly killed by a leukocyte that expresses Fc receptors, such as a natural killer cell, macrophage or neutrophil.

'Humanized' mice

Immunodeficient mice engrafted with human haematopoietic cells or tissues, or mice that transgenically express human genes.

Haemoperfusion

A process in which proteins, drugs or other materials are removed from the blood, and which is achieved by perfusing the blood over a filter or an absorbing substance.

Mixed xenogeneic chimerism

A state of coexistence between the recipient and xenogeneic donor haematopoietic cells.

Anergy

A state of immune unresponsiveness. Anergic T cells or B cells do not respond to their cognate antigens.

Receptor editing

A process that involves secondary rearrangements of B-cell receptor genes and the replacement of existing immunoglobulin molecules (mostly of the light chains), which results in the generation of a new antigen receptor with altered specificity.

Sertoli cell

A sustentacular cell in a seminiferous tubule of the testis that nurtures developing sperm cells during spermatogenesis.

Donor-specific transfusion

(DST). A treatment for inducing transplant tolerance, which involves infusion of cells into a transplant recipient from a donor that also provides the organ or tissue for the recipient.

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Yang, YG., Sykes, M. Xenotransplantation: current status and a perspective on the future. Nat Rev Immunol 7, 519–531 (2007). https://doi.org/10.1038/nri2099

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