Current Advance of Xenotransplantation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

DU Bingqing , MAI Gang , CHEN Yonghua , XIANG Guangming , GONG Jun , ZHENG Zhenjiang.

Department of Hepatobiliopancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, ChinaCorresponding Author: MAI Gang, E-mail: dbq666906@sohu.com;

Corresponding author：

Keywords：

Xenotransplantation; Hyperacute rejection; Acute rejection; Chronic rejecion; Transgenic pig; Xenotolerance

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Objective　 To summarize the current advance of xenotransplantation.
Methods 　Relevant literatures about current advance of xenotransplantation published recently domestic and abroad were collected and reviewed.
Results 　Major progress of xenotransplantation had been made in the understanding of xenoimmunobiology in the last two decades and in the threshold of clinical application. However, many problems of immunological rejection were still needed to be explored and resolved.
Conclusion 　Xenotransplantation as a transplantation source has an extensive potential to resolve the shortage of transplanted organs for end-stage organ failure, how to suppress rejection and prolong survival of grafts more effectively is a focal point of search in the future.

Citation： DU Bingqing,MAI Gang,CHEN Yonghua,XIANG Guangming,GONG Jun,ZHENG Zhenjiang.. Current Advance of Xenotransplantation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(4): 338-342. doi: Copy

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. 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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Current Advance of Xenotransplantation

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