Xenotransplantation: An Overview of the Field

  • Veronica Tisato
  • Emanuele CozziEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 885)


Xenotransplantation, the transplantation of cells, tissues, or organs between different species, has the potential to overcome the current shortage of human organs and tissues for transplantation. In the last decade, the progress made in the field is remarkable, suggesting that clinical xenotransplantation procedures, particularly those involving cells, may become a reality in the not-too-distant future. However, several hurdles remain, mainly immunological barriers, physiological discrepancies, and safety issues, making xenotransplantion a complex and multidisciplinary discipline.

Key words

Xenotransplantation Transgenic animals Hyperacute rejection Acute humoral xenograft rejection Cellular rejection Cellular transplantation Molecular incompatibility Tolerance Zoonoses 



The authors would like to thank the EU FP6 Integrated Project “Xenome” (, contract n° LSHB-CT-2006-037377 and the Consortium for Research in Organ Transplantation (CORIT, Padua, Italy) for their support. Special thanks to Dr. Michela Seveso, Dr. Marta Vadori, and Dr Federica Besenzon for their review of the manuscript.


  1. 1.
  2. 2.
  3. 3.
    Leor J, Aboulafia-Etzion S, Dar A, Shapiro L, Barbash IM, Battler A, Granot Y, Cohen S (2000) Bioengineered cardiac grafts: a new approach to repair the infarcted myocardium? Circulation 102:III56–III61PubMedCrossRefGoogle Scholar
  4. 4.
    Zimmermann WH, Schneiderbanger K, Schubert P, Didie M, Munzel F, Heubach JF, Kostin S, Neuhuber WL, Eschenhagen T (2002) Tissue engineering of a differentiated cardiac muscle construct. Circ Res 90:223–230PubMedCrossRefGoogle Scholar
  5. 5.
    Shimizu T, Sekine H, Yamato M, Okano T (2009) Cell sheet-based myocardial tissue engineering: new hope for damaged heart rescue. Curr Pharm Des 15:2807–2814PubMedCrossRefGoogle Scholar
  6. 6.
    Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA (2008) Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 14:213–221PubMedCrossRefGoogle Scholar
  7. 7.
    Ross EA, Williams MJ, Hamazaki T, Terada N, Clapp WL, Adin C, Ellison GW, Jorgensen M, Batich CD (2009) Embryonic stem cells proliferate and differentiate when seeded into kidney scaffolds. J Am Soc Nephrol 20:2338–2347PubMedCrossRefGoogle Scholar
  8. 8.
    Baptista PM, Orlando G, Mirmalek-Sani SH, Siddiqui M, Atala A, Soker S (2009) Whole organ decellularization—a tool for biosca­ffold fabrication and organ bioengineering. Conf Proc IEEE Eng Med Biol Soc 2009:6526–6529PubMedGoogle Scholar
  9. 9.
    Nakayama KH, Batchelder CA, Lee CI, Tarantal AF (2010) Decellularized rhesus monkey kidney as a three-dimensional scaffold for renal tissue engineering. Tissue Eng Part A 16:2207–2216PubMedCrossRefGoogle Scholar
  10. 10.
    Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, Milwid J, Kobayashi N, Tilles A, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K (2010) Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16:814–820PubMedCrossRefGoogle Scholar
  11. 11.
    Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, Kotton D, Vacanti JP (2010) Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 16:927–933PubMedCrossRefGoogle Scholar
  12. 12.
    Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason LE (2010) Tissue-engineered lungs for in vivo implantation. Science 329:538–541PubMedCrossRefGoogle Scholar
  13. 13.
    Sandrin MS, Vaughan HA, Dabkowski PL, McKenzie IF (1993) Anti-pig IgM antibodies in human serum react predominantly with Gal(alpha 1-3)Gal epitopes. Proc Natl Acad Sci USA 90:11391–11395PubMedCrossRefGoogle Scholar
  14. 14.
    Schuurman HJ, Cheng J, Lam T (2003) Pathology of xenograft rejection: a commentary. Xenotransplantation 10:293–299PubMedCrossRefGoogle Scholar
  15. 15.
    Platt JL (2000) Acute vascular rejection. Transplant Proc 32:839–840PubMedCrossRefGoogle Scholar
  16. 16.
    McGregor CGA, Keiji Oi WRD, Tazelaar HD, Walker RC, Chandrasekaran K, Byrne GW (2008) Recovery of cardiac function after pig-to-primate orthotopic heart transplant. Am J Transplant 8(Suppl s2):205Google Scholar
  17. 17.
    Kuwaki K, Tseng YL, Dor FJ, Shimizu A, Houser SL, Sanderson TM, Lancos CJ, Prabharasuth DD, Cheng J, Moran K, Hisashi Y, Mueller N, Yamada K, Greenstein JL, Hawley RJ, Patience C, Awwad M, Fishman JA, Robson SC, Schuurman HJ, Sachs DH, Cooper DK (2005) Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 11:29–31PubMedCrossRefGoogle Scholar
  18. 18.
    Tseng YL, Kuwaki K, Dor FJ, Shimizu A, Houser S, Hisashi Y, Yamada K, Robson SC, Awwad M, Schuurman HJ, Sachs DH, Cooper DK (2005) alpha1,3-Galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation 80:1493–1500PubMedCrossRefGoogle Scholar
  19. 19.
    Baldan N, Rigotti P, Calabrese F, Cadrobbi R, Dedja A, Iacopetti I, Boldrin M, Seveso M, Dall’Olmo L, Frison L, De Benedictis G, Bernardini D, Thiene G, Cozzi E, Ancona E (2004) Ureteral stenosis in HDAF pig-to-primate renal xenotransplantation: a phenomenon related to immunological events? Am J Transplant 4:475–481PubMedCrossRefGoogle Scholar
  20. 20.
    Shimizu A, Hisashi Y, Kuwaki K, Tseng YL, Dor FJ, Houser SL, Robson SC, Schuurman HJ, Cooper DK, Sachs DH, Yamada K, Colvin RB (2008) Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons. Am J Pathol 172:1471–1481PubMedCrossRefGoogle Scholar
  21. 21.
    Lin CC, Ezzelarab M, Shapiro R, Ekser B, Long C, Hara H, Echeverri G, Torres C, Watanabe H, Ayares D, Dorling A, Cooper DK (2010) Recipient tissue factor expression is associated with consumptive coagulopathy in pig-to-primate kidney xenotransplantation. Am J Transplant 10:1556–1568PubMedCrossRefGoogle Scholar
  22. 22.
    Sullivan JA, Oettinger HF, Sachs DH, Edge AS (1997) Analysis of polymorphism in porcine MHC class I genes: alterations in signals re­cognized by human cytotoxic lymphocytes. J Immunol 159:2318–2326PubMedGoogle Scholar
  23. 23.
    Forte P, Lilienfeld BG, Baumann BC, Seebach JD (2005) Human NK cytotoxicity against porcine cells is triggered by NKp44 and NKG2D. J Immunol 175:5463–5470PubMedGoogle Scholar
  24. 24.
    Schneider MK, Seebach JD (2008) Current cellular innate immune hurdles in pig-to-primate xenotransplantation. Curr Opin Organ Transplant 13:171–177PubMedCrossRefGoogle Scholar
  25. 25.
    Goto M, Tjernberg J, Dufrane D, Elgue G, Brandhorst D, Ekdahl KN, Brandhorst H, Wennberg L, Kurokawa Y, Satomi S, Lambris JD, Gianello P, Korsgren O, Nilsson B (2008) Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation. Xenotransplantation 15:225–234PubMedCrossRefGoogle Scholar
  26. 26.
    van der Windt DJ, Bottino R, Casu A, Campanile N, Cooper DK (2007) Rapid loss of intraportally transplanted islets: an overview of pathophysiology and preventive strategies. Xenotransplantation 14:288–297PubMedCrossRefGoogle Scholar
  27. 27.
    Hering BJ, Walawalkar N (2009) Pig-to-nonhuman primate islet xenotransplantation. Transpl Immunol 21:81–86PubMedCrossRefGoogle Scholar
  28. 28.
    Dufrane D, Goebbels RM, Gianello P (2010) Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months with­out immunosuppression. Transplantation 90:1054–1062PubMedCrossRefGoogle Scholar
  29. 29.
    Komoda H, Miyagawa S, Kubo T, Kitano E, Kitamura H, Omori T, Ito T, Matsuda H, Shirakura R (2004) A study of the xenoantigenicity of adult pig islets cells. Xenotransplantation 11:237–246PubMedCrossRefGoogle Scholar
  30. 30.
    Bennet W, Bjorkland A, Sundberg B, Davies H, Liu J, Holgersson J, Korsgren O (2000) A comparison of fetal and adult porcine islets with regard to Gal alpha (1,3)Gal expression and the role of human immunoglobulins and complement in islet cell cytotoxicity. Transplantation 69:1711–1717PubMedCrossRefGoogle Scholar
  31. 31.
    Rayat GR, Rajotte RV, Hering BJ, Binette TM, Korbutt GS (2003) In vitro and in vivo expression of Galalpha-(1,3)Gal on porcine islet cells is age dependent. J Endocrinol 177:127–135PubMedCrossRefGoogle Scholar
  32. 32.
    Rayat GR, Rajotte RV, Elliott JF, Korbutt GS (1998) Expression of Gal alpha(1,3)gal on neonatal porcine islet beta-cells and susceptibility to human antibody/complement lysis. Diabetes 47:1406–1411PubMedCrossRefGoogle Scholar
  33. 33.
    Schulte Am Esch J 2nd, Robson SC, Knoefel WT, Hosch SB, Rogiers X (2005) O-linked glycosylation and functional incompatibility of porcine von Willebrand factor for human platelet GPIb receptors. Xenotransplantation 12:30–37PubMedCrossRefGoogle Scholar
  34. 34.
    Roussel JC, Moran CJ, Salvaris EJ, Nandurkar HH, d’Apice AJ, Cowan PJ (2008) Am Pig thrombomodulin binds human thrombin but is a poor cofactor for activation of human protein C and TAFI. Am J Transplant 8:1101–1112PubMedCrossRefGoogle Scholar
  35. 35.
    Kopp CW, Siegel JB, Hancock WW, Anrather J, Winkler H, Geczy CL, Kaczmarek E, Bach FH, Robson SC (1997) Effect of porcine endothelial tissue factor pathway inhibitor on human coagulation factors. Transplantation 63:749–758PubMedCrossRefGoogle Scholar
  36. 36.
    Kopp CW, Robson SC, Siegel JB, Anrather J, Winkler H, Grey S, Kaczmarek E, Bach FH, Geczy CL (1998) Regulation of monocyte tissue factor activity by allogeneic and xenogeneic endothelial cells. Thromb Haemost 79:529–538PubMedGoogle Scholar
  37. 37.
    Lee KF, Salvaris EJ, Roussel JC, Robson SC, d’Apice AJ, Cowan PJ (2008) Recombinant pig TFPI efficiently regulates human tissue factor pathways. Xenotransplantation 15:191–197PubMedCrossRefGoogle Scholar
  38. 38.
    Lin CC, Ezzelarab M, Hara H, Long C, Lin CW, Dorling A, Cooper DK (2010) Atorvastatin or transgenic expression of TFPI inhibits coagulation initiated by anti-nonGal IgG binding to porcine aortic endothelial cells. J Thromb Haemost 8:2001–2010PubMedCrossRefGoogle Scholar
  39. 39.
    Lee H, Lee B, Kim Y, Paik N, Rho H (2011) Characterization of transgenic pigs that express human decay accelerating factor and cell membrane-tethered human tissue factor pathway inhibitor. Reprod Domest Anim 46:325–332PubMedCrossRefGoogle Scholar
  40. 40.
    Chen D, Riesbeck K, Kemball-Cook G, McVey JH, Tuddenham EG, Lechler RI, Dorling A (1999) Inhibition of tissue factor-dependent and -independent coagulation by cell surface expression of novel anticoagulant fusion proteins. Transplantation 67:467–474PubMedCrossRefGoogle Scholar
  41. 41.
    Miwa Y, Yamamoto K, Onishi A, Iwamoto M, Yazaki S, Haneda M, Iwasaki K, Liu D, Ogawa H, Nagasaka T, Uchida K, Nakao A, Kadomatsu K, Kobayashi T (2010) Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation. Xenotransplantation 17:26–37PubMedCrossRefGoogle Scholar
  42. 42.
    Crikis S, Lu B, Murray-Segal LM, Selan C, Robson SC, D’Apice AJ, Nandurkar HH, Cowan PJ, Dwyer KM (2010) Transgenic overexpression of CD39 protects against renal ischemia-reperfusion and transplant vascular injury. Am J Transplant 10:2586–2595PubMedCrossRefGoogle Scholar
  43. 43.
    Dwyer KM, Robson SC, Nandurkar HH, Campbell DJ, Gock H, Murray-Segal LJ, Fisicaro N, Mysore TB, Kaczmarek E, Cowan PJ, d’Apice AJ (2004) Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation. J Clin Invest 113:1440–1446PubMedGoogle Scholar
  44. 44.
    Cowan PJ, Robson SC, D’Apice AJ (2011) Controlling coagulation dysregulation in xenotransplantation. Curr Opin Organ Transplant 16:214–221PubMedCrossRefGoogle Scholar
  45. 45.
    Lin CC, Cooper DK, Dorling A (2009) Coagulation dysregulation as a barrier to xenotransplantation in the primate. Transpl Immunol 21:75–80PubMedCrossRefGoogle Scholar
  46. 46.
    Vial CM, Ostlie DJ, Bhatti FN, Cozzi E, Goddard M, Chavez GP, Wallwork J, White DJ, Dunning JJ (2000) Life supporting function for over one month of a transgenic porcine heart in a baboon. J Heart Lung Transplant 19:224–229PubMedCrossRefGoogle Scholar
  47. 47.
    Soin B, Smith KG, Zaidi A, Cozzi E, Bradley JR, Ostlie DJ, Lockhart A, White DJ, Friend PJ (2001) Physiological aspects of pig-to-primate renal xenotransplantation. Kidney Int 60:1592–1597PubMedCrossRefGoogle Scholar
  48. 48.
    van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C, He J, Murase N, Hara H, Ball S, Loveland BE, Ayares D, Lakkis FG, Cooper DK, Trucco M (2009) Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant 9:2716–2726PubMedCrossRefGoogle Scholar
  49. 49.
    Daggett CW, Yeatman M, Lodge AJ, Chen EP, Linn SS, Gullotto C, Frank MM, Platt JL, Davis RD (1998) Total respiratory support from swine lungs in primate recipients. J Thorac Cardiovasc Surg 115:19–27PubMedCrossRefGoogle Scholar
  50. 50.
    Cooper DK, Keogh AM, Brink J, Corris PA, Klepetko W, Pierson RN, Schmoeckel M, Shirakura R, Warner Stevenson L (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. J Heart Lung Transplant 19:1125–1165PubMedCrossRefGoogle Scholar
  51. 51.
    Pfeiffer S, Zorn GL 3rd, Blair KS, Farley SM, Wu G, Schuurman HJ, White DJ, Azimzadeh AM, Pierson RN 3rd (2005) Hyperacute lung rejection in the pig-to-human model 4: evidence for complement and antibody independent mechanisms. Transplantation 79:662–671PubMedCrossRefGoogle Scholar
  52. 52.
    Ibrahim Z, Busch J, Awwad M, Wagner R, Wells K, Cooper DK (2006) Selected physiologic compatibilities and incompatibilities between human and porcine organ systems. Xenotransplantation 13:488–499PubMedCrossRefGoogle Scholar
  53. 53.
    Ramirez P, Chavez R, Majado M, Munitiz V, Munoz A, Hernandez Q, Palenciano CG, Pino-Chavez G, Loba M, Minguela A, Yelamos J, Gago MR, Vizcaino AS, Asensi H, Cayuela MG, Segura B, Marin F, Rubio A, Fuente T, Robles R, Bueno FS, Sansano T, Acosta F, Rodriguez JM, Navarro F, Cabezuelo J, Cozzi E, White DJ, Calne RY, Parrilla P (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 70:989–998PubMedCrossRefGoogle Scholar
  54. 54.
    Ramirez P, Montoya MJ, Rios A, Garcia Palenciano C, Majado M, Chavez R, Munoz A, Fernandez OM, Sanchez A, Segura B, Sansano T, Acosta F, Robles R, Sanchez F, Fuente T, Cascales P, Gonzalez F, Ruiz D, Martinez L, Pons JA, Rodriguez JI, Yelamos J, Cowan P, d’Apice A, Parrilla P (2005) Prevention of hyperacute rejection in a model of orthotopic liver xenotransplantation from pig to baboon using polytransgenic pig livers (CD55, CD59, and H-transferase). Transplant Proc 37:4103–4106PubMedCrossRefGoogle Scholar
  55. 55.
    Ekser B, Gridelli B, Tector AJ, Cooper DK (2009) Pig liver xenotransplantation as a bridge to allotransplantation: which patients might benefit? Transplantation 88:1041–1049PubMedCrossRefGoogle Scholar
  56. 56.
    Swindle MM (1998) Defining appropriate health status and management programs for specific-pathogen-free swine for xenotransplantation. Ann N Y Acad Sci 862:111–120PubMedCrossRefGoogle Scholar
  57. 57.
    Clemenceau B, Lalain S, Martignat L, Sai P (1999) Porcine endogenous retroviral mRNAs in pancreas and a panel of tissues from specific pathogen-free pigs. Diabetes Metab 25: 518–525PubMedGoogle Scholar
  58. 58.
    Patience C, Takeuchi Y, Weiss RA (1997) Infection of human cells by an endogenous retrovirus of pigs. Nat Med 3:282–286PubMedCrossRefGoogle Scholar
  59. 59.
    Martin U, Kiessig V, Blusch JH, Haverich A, von der Helm K, Herden T, Steinhoff G (1998) Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells. Lancet 352:692–694PubMedCrossRefGoogle Scholar
  60. 60.
    Bartosch B, Stefanidis D, Myers R, Weiss R, Patience C, Takeuchi Y (2004) Evidence and consequence of porcine endogenous retrovirus recombination. J Virol 78:13880–13890PubMedCrossRefGoogle Scholar
  61. 61.
    Meije Y, Tonjes RR, Fishman JA (2010) Retroviral restriction factors and infectious risk in xenotransplantation. Am J Transplant 10:1511–1516PubMedCrossRefGoogle Scholar
  62. 62.
    Valdes-Gonzalez R, Dorantes LM, Bracho-Blanchet E, Rodriguez-Ventura A, White DJ (2010) No evidence of porcine endogenous retrovirus in patients with type 1 diabetes after long-term porcine islet xenotransplantation. J Med Virol 82:331–334PubMedCrossRefGoogle Scholar
  63. 63.
    Di Nicuolo G, D’Alessandro A, Andria B, Scuderi V, Scognamiglio M, Tammaro A, Mancini A, Cozzolino S, Di Florio E, Bracco A, Calise F, Chamuleau RA (2010) 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 17:431–439PubMedCrossRefGoogle Scholar
  64. 64.
    Mueller NJ, Barth RN, Yamamoto S, Kitamura H, Patience C, Yamada K, Cooper DK, Sachs DH, Kaur A, Fishman JA (2002) Activation of cytomegalovirus in pig-to-primate organ xenotransplantation. J Virol 76:4734–4740PubMedCrossRefGoogle Scholar
  65. 65.
    Ehlers B, Ulrich S, Goltz M (1999) Detection of two novel porcine herpesviruses with high similarity to gammaherpesviruses. J Gen Virol 80(Pt 4):971–978PubMedGoogle Scholar
  66. 66.
    Santoni F, Lindner I, Caselli E, Goltz M, Di Luca D, Ehlers B (2006) Molecular interactions between porcine and human gammaherpesviruses: implications for xenografts? Xenotransplantation 13:308–317PubMedCrossRefGoogle Scholar
  67. 67.
    Oldmixon BA, Wood JC, Ericsson TA, Wilson CA, White-Scharf ME, Andersson G, Greenstein JL, Schuurman HJ, Patience C (2002) Porcine endogenous retrovirus transmission characteristics of an inbred herd of miniature swine. J Virol 76:3045–3048PubMedCrossRefGoogle Scholar
  68. 68.
    Mattiuzzo G, Ivol S, Takeuchi Y (2010) Regulation of porcine endogenous retrovirus release by porcine and human tetherins. J Virol 84:2618–2622PubMedCrossRefGoogle Scholar
  69. 69.
    Ramsoondar J, Vaught T, Ball S, Mendicino M, Monahan J, Jobst P, Vance A, Duncan J, Wells K, Ayares D (2009) Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs. Xenotransplantation 16:164–180PubMedCrossRefGoogle Scholar
  70. 70.
    Dieckhoff B, Petersen B, Kues WA, Kurth R, Niemann H, Denner J (2008) Knockdown of porcine endogenous retrovirus (PERV) expression by PERV-specific shRNA in transgenic pigs. Xenotransplantation 15:36–45PubMedCrossRefGoogle Scholar
  71. 71.
    Miyagawa S, Nakatsu S, Hazama K, Nakagawa T, Kondo A, Matsunami K, Yamamoto A, Yamada J, Miyazawa T, Shirakura R (2006) A novel strategy for preventing PERV transmission to human cells by remodeling the viral envelope glycoprotein. Xenotransplantation 13:258–263PubMedCrossRefGoogle Scholar
  72. 72.
    Ekser B, Long C, Echeverri GJ, Hara H, Ezzelarab M, Lin CC, de Vera ME, Wagner R, Klein E, Wolf RF, Ayares D, Cooper DK, Gridelli B (2010) Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants: clinical relevance. Am J Transplant 10:273–285PubMedCrossRefGoogle Scholar
  73. 73.
    Gaca JG, Lesher A, Aksoy O, Gonzalez-Stawinski GV, Platt JL, Lawson JH, Parker W, Davis RD (2002) Disseminated intravascular coagulation in association with pig-to-primate pulmonary xenotransplantation. Transplantation 73:1717–1723PubMedCrossRefGoogle Scholar
  74. 74.
    Gonzalez-Stawinski GV, Daggett CW, Lau CL, Karoor S, Love SD, Logan JS, Gaca JG, Parker W, Davis RD Jr (2002) Non-anti-Gal alpha1-3Gal antibody mechanisms are sufficient to cause hyperacute lung dysfunction in pulmonary xenotransplantation. J Am Coll Surg 194:765–773PubMedCrossRefGoogle Scholar
  75. 75.
    Nguyen BH, Zwets E, Schroeder C, Pierson RN 3rd, Azimzadeh AM (2005) Beyond antibody-mediated rejection: hyperacute lung rejection as a paradigm for dysregulated inflammation. Curr Drug Targets Cardiovasc Haematol Disord 5:255–269PubMedCrossRefGoogle Scholar
  76. 76.
    Nguyen BN, Azimzadeh AM, Zhang T, Wu G, Schuurman HJ, Sachs DH, Ayares D, Allan JS, Pierson RN 3rd (2007) Life-supporting function of genetically modified swine lungs in baboons. J Thorac Cardiovasc Surg 133:1354–1363PubMedCrossRefGoogle Scholar
  77. 77.
    Cardona K, Korbutt GS, Milas Z, Lyon J, Cano J, Jiang W, Bello-Laborn H, Hacquoil B, Strobert E, Gangappa S, Weber CJ, Pearson TC, Rajotte RV, Larsen CP (2006) Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 12:304–306PubMedCrossRefGoogle Scholar
  78. 78.
    Hering BJ, Wijkstrom M, Graham ML, Hardstedt M, Aasheim TC, Jie T, Ansite JD, Nakano M, Cheng J, Li W, Moran K, Christians U, Finnegan C, Mills CD, Sutherland DE, Bansal-Pakala P, Murtaugh MP, Kirchhof N, Schuurman HJ (2006) Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 12:301–303PubMedCrossRefGoogle Scholar
  79. 79.
    Hecht G, Eventov-Friedman S, Rosen C, Shezen E, Tchorsh D, Aronovich A, Freud E, Golan H, El-Hasid R, Katchman H, Hering BJ, Zung A, Kra-Oz Z, Shaked-Mishan P, Yusim A, Shtabsky A, Idelevitch P, Tobar A, Harmelin A, Bachar-Lustig E, Reisner Y (2009) Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman ­primate model. Proc Natl Acad Sci USA 106:8659–8664PubMedCrossRefGoogle Scholar
  80. 80.
    Fink JS, Schumacher JM, Ellias SL, Palmer EP, Saint-Hilaire M, Shannon K, Penn R, Starr P, VanHorne C, Kott HS, Dempsey PK, Fischman AJ, Raineri R, Manhart C, Dinsmore J, Isacson O (2000) Porcine xenografts in Parkinson’s disease and Huntington’s disease patients: preliminary results. Cell Transplant 9:273–278PubMedGoogle Scholar
  81. 81.
    Badin RA, Padoan A, Vadori M, Boldrin M, De Benedictis GM, Fante F, Sgarabotto D, Jan C, Daguin V, Naveilhan P, Neveu I, Soullilou JP, Vanhove B, Plat M, Botté F, Venturi F, Denaro L, Seveso M, Manara R, Zampieri P, D’Avella D, Rubello D, Ancona E, Hantraye P, Cozzi E (2010) Porcine embryonic xenografts transgenic for CTLA4-Ig enable longterm Recovery in parkinsonian macaques. Am J Transplant 10(Suppl s4):208Google Scholar
  82. 82.
    Lynch RJ, Platt JL (2009) Escaping from rejection. Transplantation 88:1233–1236PubMedCrossRefGoogle Scholar
  83. 83.
    Koch CA, Khalpey ZI, Platt JL (2004) Accommodation: preventing injury in transplantation and disease. J Immunol 172:5143–5148PubMedGoogle Scholar
  84. 84.
    Ildstad ST, Sachs DH (1984) Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307:168–170PubMedCrossRefGoogle Scholar
  85. 85.
    Sharabi Y, Aksentijevich I, Sundt TM 3rd, Sachs DH, Sykes M (1990) Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen. J Exp Med 172:195–202PubMedCrossRefGoogle Scholar
  86. 86.
    Yang YG, deGoma E, Ohdan H, Bracy JL, Xu Y, Iacomini J, Thall AD, Sykes M (1998) Tolerization of anti-Galalpha1-3Gal natural antibody-forming B cells by induction of mixed chimerism. J Exp Med 187:1335–1342PubMedCrossRefGoogle Scholar
  87. 87.
    Abe M, Qi J, Sykes M, Yang YG (2002) Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier. Blood 99:3823–3829PubMedCrossRefGoogle Scholar
  88. 88.
    Murakami T, Cosimi AB, Kawai T (2009) Mixed chimerism to induce tolerance: lessons learned from nonhuman primates. Transplant Rev (Orlando) 23:19–24CrossRefGoogle Scholar
  89. 89.
    Barth RN, Yamamoto S, LaMattina JC, Kumagai N, Kitamura H, Vagefi PA, Awwad M, Colvin RB, Cooper DK, Sykes M, Sachs DH, Yamada K (2003) Xenogeneic thymokidney and thymic tissue transplantation in a pig-to-baboon model: I evidence for pig-specific T-cell unresponsiveness. Transplantation 75:1615–1624PubMedCrossRefGoogle Scholar
  90. 90.
    Yamada K, Yazawa K, Shimizu A, Iwanaga T, Hisashi Y, Nuhn M, O’Malley P, Nobori S, Vagefi PA, Patience C, Fishman J, Cooper DK, Hawley RJ, Greenstein J, Schuurman HJ, Awwad M, Sykes M, Sachs DH (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. Nat Med 11:32–34PubMedCrossRefGoogle Scholar
  91. 91.
    Griesemer AD, Hirakata A, Shimizu A, Moran S, Tena A, Iwaki H, Ishikawa Y, Schule P, Arn JS, Robson SC, Fishman JA, Sykes M, Sachs DH, Yamada K (2009) Results of gal-knockout porcine thymokidney xenografts. Am J Transplant 9:2669–2678PubMedCrossRefGoogle Scholar
  92. 92.
    Muller YD, Golshayan D, Ehirchiou D, Wekerle T, Seebach JD, Buhler LH (2009) T regulatory cells in xenotransplantation. Xeno­transplantation 16:121–128PubMedCrossRefGoogle Scholar
  93. 93.
    Dons EM, Raimondi G, Cooper DK, Thomson AW (2010) Non-human primate regulatory T cells: current biology and implications for transplantation. Transplantation 90:811–816PubMedCrossRefGoogle Scholar
  94. 94.
    Porter CM, Bloom ET (2005) Human CD4+CD25+ regulatory T cells suppress anti-porcine xenogeneic responses. Am J Transplant 5:2052–2057PubMedCrossRefGoogle Scholar
  95. 95.
  96. 96.
  97. 97.
  98. 98.
    Sgroi A, Buhler LH, Morel P, Sykes M, Noel L (2010) International human xenotransplantation inventory. Transplantation 90:597–603PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Surgical and Gastroenterological SciencesUniversity of PaduaPaduaItaly
  2. 2.CORIT (Consortium for Research in Organ Transplantation)PaduaItaly
  3. 3.Direzione Sanitaria, Padua General HospitalPaduaItaly

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