• 四川大學(xué)華西醫(yī)院肝膽胰外科(成都 610041);

目的 　總結(jié)異種器官移植的新進(jìn)展。
方法 　分析近年來異種器官移植進(jìn)展的文獻(xiàn)報(bào)道。
結(jié)果 　隨著免疫生物學(xué)的深入研究，異種器官移植取得了長足的進(jìn)步，并開始應(yīng)用于臨床,但免疫排斥反應(yīng)的諸多問題仍在探尋之中。
結(jié)論 　異種移植為解決器官衰竭患者移植器官短缺的問題展現(xiàn)了廣闊的前景，如何更有效地抑制排斥反應(yīng)及延長移植物生存期是今后研究的重點(diǎn)。

引用本文： 杜冰清,麥剛,陳擁華,向光明,龔軍,鄭振江. 異種器官移植的新進(jìn)展. 中國普外基礎(chǔ)與臨床雜志, 2010, 17(4): 338-342. doi: 復(fù)制

1. Matsunari H, Nagashima H. Application of genetically modified and cloned pigs in translational research [J]. J Reprod Dev, 2009; 55(3): 225-230.
2. 　Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future [J]. Nat Rev Immunol, 2007; 7(7): 519-531.
3. 　Niemann H, Verhoeyen E, Wonigeit K, et al. Cytomegalovirus early promoter induced expression of hCD59 in porcine organs provides protection against hyperacute rejection [J]. Transplantation, 2001; 72(12): 1898-1906.
4. 　Kolber-Simonds D, Lai L, Watt SR, et al. Production of α-1,3-galactosyltransferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations [J]. Proc Natl Acad Sci USA, 2004; 101(19): 7335-7340.
5. 　Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future [J]. Nat Rev Immunol, 2007; 7(7): 519-531.
6. 　Lin CC, Cooper DK, Dorling A. Coagulation dysregulation as a barrier to xenotransplantation in the primate [J]. Transpl Immunol, 2009; 21(2): 75-80.
7. 　Sprangers B, Waer M, Billiau AD. Xenotransplantation: where are we in 2008? [J]. Kidney Int, 2008; 74(1): 14-21.
8. 　Cadili A, Kneteman N. The role of macrophages in xenograft rejection [J]. Transplant Proc, 2008; 40(10): 3289-3293.
9. 　Maeda A, Goto M, Zhang J, et al. Immunosuppression with FTY720 and cyclosporine A inhibits rejection of adult porcine islet xenografts in rats [J]. Transplantation, 2003; 75(8): 1409-1414.
10. 　Weiss MJ, Ng CY, Madsen JC. Tolerance, xenotransplantation: future therapies [J]. Surg Clin North Am, 2006; 86(5): 1277-1296.
11. 　Ekser B, Cooper DK. Update: cardiac xenotransplantation [J]. Curr Opin Organ Transplant, 2008; 13(5): 531-535.
12. 　Ma Y, He KM, Garcia B, et al. Adoptive transfer of double negative T regulatory cells induces B-cell death in vivo and alters rejection pattern of rat-to-mouse heart transplantation [J]. Xenotransplantation, 2008; 15(1): 56-63.
13. 　Muller YD, Golshayan D, Ehirchiou D, et al. T regulatory cells in xenotransplantation [J]. Xenotransplantation, 2009; 16(3): 121-128.
14. 　Weiss EH, Lilienfeld BG, Müller S, et al. HLA-E/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity [J]. Transplantation, 2009; 87(1): 35-43.
15. 　Yi S, Hawthorne WJ, Lehnert AM, et al. T cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts [J]. J Immunol, 2003; 170(5): 2750-2758.
16. 　Yi S, Ouyang L, Ha H, et al. Involvement of CCR5 signaling in macrophage recruitment to porcine islet xenografts [J]. Transplantation, 2005; 80(10): 1468-1475.
17. 　Cowan PJ. Coagulation and the xenograft endothelium [J]. Xenotransplantation, 2007; 14(1): 7-12.
18. 　Cowan PJ, Roussel JC, d’Apice AJ. The vascular and coagulation issues in xenotransplantation [J]. Curr Opin Organ Transplant, 2009; 14(2): 161-167.
19. 　Crikis S, Cowan PJ, d’Apice AJ. Intravascular thrombosis in discordant xenotransplantation [J]. Transplantation, 2006; 82(9): 1119-1123.
20. 　Cooper DK, Dorling A, Pierson RN 3rd, et al. Alpha 1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? [J]. Transplantation, 2007; 84(1): 1-7.
21. 　Denner J. Is porcine endogenous retrovirus (PERV) transmission still relevant? [J]. Transplant Proc, 2008; 40(2): 587-589.
22. 　Scobie L, Takeuchi Y. Porcine endogenous retrovirus and other viruses in xenotransplantation [J]. Curr Opin Organ Transplant, 2009; 14(2): 175-179.
23. 　Hering BJ, Wijkstrom M, Graham ML, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates [J]. Nat Med， 2006; 12(3): 301-303.
24. 　Smith RM, Mandel TE. Pancreatic islet xenotransplantation: the potential for tolerance induction [J]. Immunol Today, 2000; 21(1): 42-48.
25. 　Cardona K, Korbutt GS, Milas Z, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways [J]. Nat Med, 2006; 12(3): 304-306.
26. 　Kumagai-Braesch M, Ekberg H, Wang F, et al. Anti-LFA-1 improves pig islet xenograft function in diabetic mice when long-term acceptance is induced by CTLA4Ig/anti-CD40L [J]. Transplantation, 2007; 83(9): 1259-1267.
27. 　Dufrane D, Goebbels RM, Saliez A, et al. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept [J]. Transplantation, 2006; 81(9): 1345-1353.
28. 　Mayor S. Australian team to transplant pig islet cells into patients with unstable diabetes [J]. BMJ, 2009; 339: b3089.
29. 　Casu A, Bottino R, Balamurugan AN, et al. Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice [J]. Diabetologia, 2008; 51(1): 120-129.
30. 　Zhu X, Dor FJ, Cooper DK. Pig-to-non-human primate heart transplantation: immunologic progress over 20 years [J]. J Heart Lung Transplant, 2007; 26(3): 210-218.
31. 　Kuwaki K, Tseng YL, Dor FJ, et al. Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience [J]. Nat Med, 2005; 11(1): 29-31.
32. 　Hammerman MR. Xenotransplantation of renal primordial [J]. Curr Opin Nephrol Hypertens, 2002; 11(1): 11-16.
33. 　Chen G, Qian H, Starzl T, et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys [J]. Nat Med, 2005; 11(12): 1295-1298.
34. 　Knosalla C, Yazawa K, Behdad A, et al. Renal and cardiac endothelial heterogeneity impact acute vascular rejection in pig-to-baboon xenotransplantation [J]. Am J Transplant, 2009; 9(5): 1006-1016.
35. 　Yamada K, Yazawa K, Shimizu A, et al. 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 [J]. Nat Med, 2005; 11(1): 32-34.
36. 　Ekser B, Rigotti P, Gridelli B, et al. Xenotransplantation of solid organs in the pig-to-primate model [J]. Transpl Immunol, 2009; 21(2): 87-92.
37. 　Hara H, Gridelli B, Lin YJ, et al. Liver xenografts for the treatment of acute liver failure: clinical and experimental experience and remaining immunologic barriers [J]. Liver Transpl, 2008; 14(4): 425-434.
38. 　Pascher A, Sauer IM, Hammer C, et al. Extracorporeal liver perfusion as hepatic assist in acute liver failure: a review of world experience [J]. Xenotransplantation, 2002; 9(5): 309-324.
39. 　Horslen SP, Hammel JM, Fristoe LW, et al. Extracorporeal liver perfusion using human and pig livers for acute liver failure [J]. Transplantation， 2000; 70(10): 1472-1478.
40. 　Tector AJ, Elias N, Rosenberg L, et al. Mechanisms of resistance to injury in pig livers perfused with blood from patients in liver failure [J]. Transplant Proc, 1997; 29(1-2): 966-969.
41. 　Platt JL. Xenotransplantation of the liver: is more complement control needed? [J]. Liver Transpl, 2001; 7(10): 933-934.
42. 　Rees MA, Butler AJ, Negus MC, et al. Classical pathway complement destruction is not responsible for the loss of human erythrocytes during porcine liver perfusion [J]. Transplantation, 2004; 77(9): 1416-1423.
43. 　Oldenborg PA, Zheleznyak A, Fang YF, et al. Role of CD47 as a marker of self on red blood cells [J]. Science, 2000; 288(5473): 2051-2054.
44. 　Tai HC, Zhu X, Hara H, et al. The pig-to-primate immune response: relevance for xenotransplantation [J]. Xenotransplantation, 2007; 14(3): 227-235.
  1. 1. Matsunari H, Nagashima H. Application of genetically modified and cloned pigs in translational research [J]. J Reprod Dev, 2009; 55(3): 225-230.
  2. 2. 　Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future [J]. Nat Rev Immunol, 2007; 7(7): 519-531.
  3. 3. 　Niemann H, Verhoeyen E, Wonigeit K, et al. Cytomegalovirus early promoter induced expression of hCD59 in porcine organs provides protection against hyperacute rejection [J]. Transplantation, 2001; 72(12): 1898-1906.
  4. 4. 　Kolber-Simonds D, Lai L, Watt SR, et al. Production of α-1,3-galactosyltransferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations [J]. Proc Natl Acad Sci USA, 2004; 101(19): 7335-7340.
  5. 5. 　Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future [J]. Nat Rev Immunol, 2007; 7(7): 519-531.
  6. 6. 　Lin CC, Cooper DK, Dorling A. Coagulation dysregulation as a barrier to xenotransplantation in the primate [J]. Transpl Immunol, 2009; 21(2): 75-80.
  7. 7. 　Sprangers B, Waer M, Billiau AD. Xenotransplantation: where are we in 2008? [J]. Kidney Int, 2008; 74(1): 14-21.
  8. 8. 　Cadili A, Kneteman N. The role of macrophages in xenograft rejection [J]. Transplant Proc, 2008; 40(10): 3289-3293.
  9. 9. 　Maeda A, Goto M, Zhang J, et al. Immunosuppression with FTY720 and cyclosporine A inhibits rejection of adult porcine islet xenografts in rats [J]. Transplantation, 2003; 75(8): 1409-1414.
  10. 10. 　Weiss MJ, Ng CY, Madsen JC. Tolerance, xenotransplantation: future therapies [J]. Surg Clin North Am, 2006; 86(5): 1277-1296.
  11. 11. 　Ekser B, Cooper DK. Update: cardiac xenotransplantation [J]. Curr Opin Organ Transplant, 2008; 13(5): 531-535.
  12. 12. 　Ma Y, He KM, Garcia B, et al. Adoptive transfer of double negative T regulatory cells induces B-cell death in vivo and alters rejection pattern of rat-to-mouse heart transplantation [J]. Xenotransplantation, 2008; 15(1): 56-63.
  13. 13. 　Muller YD, Golshayan D, Ehirchiou D, et al. T regulatory cells in xenotransplantation [J]. Xenotransplantation, 2009; 16(3): 121-128.
  14. 14. 　Weiss EH, Lilienfeld BG, Müller S, et al. HLA-E/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity [J]. Transplantation, 2009; 87(1): 35-43.
  15. 15. 　Yi S, Hawthorne WJ, Lehnert AM, et al. T cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts [J]. J Immunol, 2003; 170(5): 2750-2758.
  16. 16. 　Yi S, Ouyang L, Ha H, et al. Involvement of CCR5 signaling in macrophage recruitment to porcine islet xenografts [J]. Transplantation, 2005; 80(10): 1468-1475.
  17. 17. 　Cowan PJ. Coagulation and the xenograft endothelium [J]. Xenotransplantation, 2007; 14(1): 7-12.
  18. 18. 　Cowan PJ, Roussel JC, d’Apice AJ. The vascular and coagulation issues in xenotransplantation [J]. Curr Opin Organ Transplant, 2009; 14(2): 161-167.
  19. 19. 　Crikis S, Cowan PJ, d’Apice AJ. Intravascular thrombosis in discordant xenotransplantation [J]. Transplantation, 2006; 82(9): 1119-1123.
  20. 20. 　Cooper DK, Dorling A, Pierson RN 3rd, et al. Alpha 1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? [J]. Transplantation, 2007; 84(1): 1-7.
  21. 21. 　Denner J. Is porcine endogenous retrovirus (PERV) transmission still relevant? [J]. Transplant Proc, 2008; 40(2): 587-589.
  22. 22. 　Scobie L, Takeuchi Y. Porcine endogenous retrovirus and other viruses in xenotransplantation [J]. Curr Opin Organ Transplant, 2009; 14(2): 175-179.
  23. 23. 　Hering BJ, Wijkstrom M, Graham ML, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates [J]. Nat Med， 2006; 12(3): 301-303.
  24. 24. 　Smith RM, Mandel TE. Pancreatic islet xenotransplantation: the potential for tolerance induction [J]. Immunol Today, 2000; 21(1): 42-48.
  25. 25. 　Cardona K, Korbutt GS, Milas Z, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways [J]. Nat Med, 2006; 12(3): 304-306.
  26. 26. 　Kumagai-Braesch M, Ekberg H, Wang F, et al. Anti-LFA-1 improves pig islet xenograft function in diabetic mice when long-term acceptance is induced by CTLA4Ig/anti-CD40L [J]. Transplantation, 2007; 83(9): 1259-1267.
  27. 27. 　Dufrane D, Goebbels RM, Saliez A, et al. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept [J]. Transplantation, 2006; 81(9): 1345-1353.
  28. 28. 　Mayor S. Australian team to transplant pig islet cells into patients with unstable diabetes [J]. BMJ, 2009; 339: b3089.
  29. 29. 　Casu A, Bottino R, Balamurugan AN, et al. Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice [J]. Diabetologia, 2008; 51(1): 120-129.
  30. 30. 　Zhu X, Dor FJ, Cooper DK. Pig-to-non-human primate heart transplantation: immunologic progress over 20 years [J]. J Heart Lung Transplant, 2007; 26(3): 210-218.
  31. 31. 　Kuwaki K, Tseng YL, Dor FJ, et al. Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience [J]. Nat Med, 2005; 11(1): 29-31.
  32. 32. 　Hammerman MR. Xenotransplantation of renal primordial [J]. Curr Opin Nephrol Hypertens, 2002; 11(1): 11-16.
  33. 33. 　Chen G, Qian H, Starzl T, et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys [J]. Nat Med, 2005; 11(12): 1295-1298.
  34. 34. 　Knosalla C, Yazawa K, Behdad A, et al. Renal and cardiac endothelial heterogeneity impact acute vascular rejection in pig-to-baboon xenotransplantation [J]. Am J Transplant, 2009; 9(5): 1006-1016.
  35. 35. 　Yamada K, Yazawa K, Shimizu A, et al. 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 [J]. Nat Med, 2005; 11(1): 32-34.
  36. 36. 　Ekser B, Rigotti P, Gridelli B, et al. Xenotransplantation of solid organs in the pig-to-primate model [J]. Transpl Immunol, 2009; 21(2): 87-92.
  37. 37. 　Hara H, Gridelli B, Lin YJ, et al. Liver xenografts for the treatment of acute liver failure: clinical and experimental experience and remaining immunologic barriers [J]. Liver Transpl, 2008; 14(4): 425-434.
  38. 38. 　Pascher A, Sauer IM, Hammer C, et al. Extracorporeal liver perfusion as hepatic assist in acute liver failure: a review of world experience [J]. Xenotransplantation, 2002; 9(5): 309-324.
  39. 39. 　Horslen SP, Hammel JM, Fristoe LW, et al. Extracorporeal liver perfusion using human and pig livers for acute liver failure [J]. Transplantation， 2000; 70(10): 1472-1478.
  40. 40. 　Tector AJ, Elias N, Rosenberg L, et al. Mechanisms of resistance to injury in pig livers perfused with blood from patients in liver failure [J]. Transplant Proc, 1997; 29(1-2): 966-969.
  41. 41. 　Platt JL. Xenotransplantation of the liver: is more complement control needed? [J]. Liver Transpl, 2001; 7(10): 933-934.
  42. 42. 　Rees MA, Butler AJ, Negus MC, et al. Classical pathway complement destruction is not responsible for the loss of human erythrocytes during porcine liver perfusion [J]. Transplantation, 2004; 77(9): 1416-1423.
  43. 43. 　Oldenborg PA, Zheleznyak A, Fang YF, et al. Role of CD47 as a marker of self on red blood cells [J]. Science, 2000; 288(5473): 2051-2054.
  44. 44. 　Tai HC, Zhu X, Hara H, et al. The pig-to-primate immune response: relevance for xenotransplantation [J]. Xenotransplantation, 2007; 14(3): 227-235.