Research Progress of Xenotransplantation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YAO Danhua ,  LI Yousheng , LI Jieshou.

Department of General Surgery， Jinling Hospital， Medical School of Nanjing University， Nanjing 210002， Jiangsu Province， China;

Corresponding author：

LI Yousheng, Email: liys@medmail.com.cn

Keywords：

Xenotransplantation; Hyperacute xenograft rejection; Transgenic; Gene knock-out

Video：

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Objective 　To summarize the research progress of xenotransplantation.
Methods 　Domestic and international publications about xenotransplantation were summarized and reviewed.
Results 　Hyperacute xenograft rejection was a huge problem for xenotransplantation， but it could be alleviated if the organs or tissues of donor were genetically modified. So far the graft survival time differed greatly due to characteristics of different organ. Conclusions 　By reviewing the studies of relevant papers about xenotransplantation， a comprehensive understanding of research background and a suitable research direction of xenotransplantation can be supplied. The graft organs or tissues from genetically modified donors are expected to avoid or alleviate hyperacute xenograft rejection.

Citation： YAO Danhua,LI Yousheng,LI Jieshou.. Research Progress of Xenotransplantation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(12): 1437-1441. doi: Copy

1.	United Network for Organ Sharing. Transplant trends[EB/OL]. 2013-3-10. http：//www. unos. org/.
2.	Eurotransplant. Annual report 2012[EB/OL]. 2013-1-1. http：//www. eurotransplant. org/.
3.	Sandrin MS， Vaughan HA， Dabkowski PL， et al. Anti-pig IgM antibodies in human serum react predominantly with Gal （alpha 1-3) Gal epitopes[J]. Proc Natl Acad Sci U S A， 1993， 90(23)：11391-11395.
4.	Macher BA， Galili U. The galalpha1， 3galbeta1， 4GlcNAc-R(alpha-Gal) epitope：a carbohydrate of unique evolution and clinicalrelevance[J]. Biochim Biophys Acta， 2008， 1780(2)：75-88.
5.	Lai L， Kolber-Simonds D， Park KW， et al. Production of alpha-1，3-galactosyltransferase knockout pigs by nuclear transfer cloning[J]. Science， 2002， 295(5557)：1089-1092.
6.	Dai Y， Vaught TD， Boone J， et al. Targeted disruption of the alpha1， 3-galactosyltransferase gene in cloned pigs[J]. Nat Biotechnol， 2002， 20(3)：251-255.
7.	Phelps CJ， Koike C， Vaught TD， et al. Production of alpha 1， 3-galactosyltransferase-deficient pigs[J]. Science， 2003， 299(5605)：411-414.
8.	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.
9.	Cooper DK， Bottino R， Satyananda V， et al. Toward clinical islet xenotransplantation—are revisions to the IXA guidelines warranted?[J]. Xenotransplantation， 2013， 20(2)：68-74.
10.	Yeh P， Ezzelarab M， Bovin N， et al. Investigation of potential carbohydrate antigen targets for human and baboon antibodies[J]. Xenotransplantation， 2010， 17(3)：197-206.
11.	Zhu B， Tong C， Guo W， et al. Synergistic suppression of pre-per-fusion of donor livers with recipient serum and cobra venom factortreatment on hyperacute rejection following liver xenotransplan-tation[J]. Acta Cir Bras， 2012， 27(5)：301-305.
12.	Salerno CT， Kulick DM， Yeh CG， et al. A soluble chimeric inhibitor of C3 and C5 convertases， complement activation blocker-2， prolongs graft survival in pig-to-rhesus monkey heart transplantation[J]. Xenotransplantation， 2002， 9(2)：125-134.
13.	Poirier N， Blancho G. Recombinant human C1-inhibitor inhibits cytotoxicity induced by allo- and xenoantibodies[J]. Transplant Proc， 2008， 40(2)：581-583.
14.	Cowan PJ， Aminian A， Barlow H， et al. Renal xenografts from triple-transgenic pigs are not hyperacutely rejected but cause coagu-lopathy in non-immunosuppressed baboons[J]. Transplantation，2000， 69(12)：2504-2515.
15.	Auchincloss H Jr， Sachs DH. Xenogeneic transplantation[J]. Annu Rev Immunol， 1998， 16：433-470.
16.	Breimer ME. Gal/non-Gal antigens in pig tissues and human non-Gal antibodies in the GalT-KO era[J]. Xenotransplantation， 2011， 18(4)：215-228.
17.	Chen G， Qian H， Starzl T， et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockoutpig kidneys[J]. Nat Med， 2005， 11(12)：1295-1298.
18.	Horvath-Arcidiacono JA， Porter CM， Bloom ET， et al. Human NK cells can lyse porcine endothelial cells independent of their expression of Galalpha(1，3)-Gal and killing is enhanced by activation of either effector or target cells[J]. Xenotransplantation， 2006， 13(4)：318-327.
19.	Ibrahim Z， Busch J， Awwad M， et al. Selected physiologic compatibilities and incompatibilities between human and porcine organ systems[J]. Xenotransplantation， 2006， 13(6)：488-499.
20.	Patience C， Takeuchi Y， Weiss RA. Infection of human cells by an endogenous retrovirus of pigs[J]. Nat Med， 1997， 3(3)：282-286.
21.	van der Laan LJ， Lockey C， Griffeth BC， et al. Infection by por-cine endogenous retrovirus after islet xenotransplantation in SCID mice[J]. Nature， 2000， 407(6800)：90-94.
22.	Paradis K， Langford G， Long Z， et al. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group[J]. Science， 1999， 285(5431)：1236-1241.
23.	Hector RD， Meikle S， Grant L， et al. Pre-screening of miniature swine may reduce the risk of transmitting human tropic recombinant porcine endogenous retroviruses[J]. Xenotransplantation， 2007， 14(3)：222-226.
24.	Ekser B， Ezzelarab M， Hara H， et al. Clinical xenotransplantation：the next medical revolution?[J]. Lancet， 2012， 379(9816)：672-683.
25.	Marigliano M， Bertera S， Grupillo M， et al. Pig-to-nonhuman primates pancreatic islet xenotransplantation：an overview[J]. Curr Diab Rep， 2011， 11(5)：402-412.
26.	van der Windt DJ， Bottino R， Kumar G， et al. Clinical islet xenotransplantation：how close are we?[J]. Diabetes， 2012， 61(12)：3046-3055.
27.	van der Windt DJ， Bottino R， Casu A， et al. Long-term controllednormoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets[J]. Am J Transplant， 2009， 9(12)：2716-2726.
28.	Dufrane D， Goebbels RM， Gianello P. Alginate macroencapsul-ation of pig islets allows correction of streptozotocin-induceddiabetes in primates up to 6 months without immunosuppression[J]. Transplantation， 2010， 90(10)：1054-1062.
29.	Luan NM， Iwata H. Xenotransplantation of islets enclosed in agarose microcapsule carrying soluble complement receptor 1[J]. Biomaterials， 2012， 33(32)：8075-8081.
30.	Shimizu A， Hisashi Y， Kuwaki K， et al. Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1， 3-galactosyltransferase gene-knockout pigs in baboons[J]. Am J Pathol， 2008， 172(6)：1471-1481.
31.	Mohiuddin MM， Corcoran PC， Singh AK， et al. B-cell depletion extends the survival of GTKO. hCD46Tg pig heart xenografts in baboons for up to 8 months[J]. Am J Transplant， 2012， 12(3)：763-771.
32.	Calne RY， White HJ， Herbertson BM， et al. Pig-to-baboon liver xenografts[J]. Lancet， 1968， 1(7553)：1176-1178.
33.	Ramirez P， Chavez R， Majado M， et al. 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[J]. Transplantation， 2000， 70(7)：989-998.
34.	Ramirez P， Montoya MJ， Ríos A， 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)[J]. Transplant Proc， 2005， 37(9)：4103-4106.
35.	Ekser B， Echeverri GJ， Hassett AC， et al. Hepatic function after genetically engineered pig liver transplantation in baboons[J]. Transplantation， 2010， 90(5)：483-493.
36.	Ekser B， Long C， Echeverri GJ， et al. Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants：clinical relevance[J]. Am J Transplant， 2010， 10(2)：273-285.
37.	Kim K， Schuetz C， Elias N， et al. Up to 9-day survival and controlof thrombocytopenia following alpha1， 3-galactosyl transferase knockout swine liver xenotransplantation in baboons[J]. Xenotr-ansplantation， 2012， 19(4)：256-264.
38.	Baldan N， Rigotti P， Calabrese F， et al. Ureteral stenosis in HDAF pig-to-primate renal xenotransplantation：a phenomenon related to immunological events?[J]. Am J Transplant， 2004， 4(4)：475-481.
39.	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.
40.	Le Bas-Bernardet S， Tillou X， Poirier N， et al. Xenotransplantation of galactosyl-transferase knockout， CD55， CD59， CD39， and fucosyl-transferase transgenic pig kidneys into baboons[J]. Transplant Proc， 2011， 43(9)：3426-3430.
41.	Yedidag EN， Fryer JP， Levi E， et al. Early histopathology of small intestinal discordant xenografts[J]. Transplantation， 1996， 62(10)：1385-1391.
42.	Kiyochi H， Kellersmann R， Blömer A， et al. Rat-to-mouse small bowel xenotransplantation：a novel model for studying acute vascular and hyperacute xenograft rejection and xenogenic cell migration[J]. Xenotransplantation， 1999， 6(1)：28-35.
43.	Lau CL， Cantu E 3rd， Gonzalez-Stawinski GV， et al. The role of antibodies and von Willebrand factor in discordant pulmonary xenotransplantation[J]. Am J Transplant， 2003， 3(9)：1065-1075.
44.	Kim YT， Lee HJ， Lee SW， et al. Pre-treatment of porcine pulm-onary xenograft with desmopressin：a novel strategy to attenuate platelet activation and systemic intravascular coagulation in an ex-vivo model of swine-to-human pulmonary xenotransplantation[J]. Xenotransplantation， 2008， 15(1)：27-35.
45.	Cantu E， Balsara KR， Li B， et al. Prolonged function of macro-phage， von Willebrand factor-deficient porcine pulmonary xenografts[J]. Am J Transplant， 2007， 7(1)：66-75.
46.	Sinis N， Haerle M， Becker ST， et al. Neuroma formation in a rat median nerve model：influence of distal stump and muscular coating[J]. Plast Reconstr Surg， 2007， 119(3)：960-966.
47.	Galeano M， Manasseri B， Risitano G， et al. A free vein graft cap influences neuroma formation after nerve transection[J]. Microsurgery， 2009， 29(7)：568-572.
48.	Lu LJ， Sun JB， Liu ZG， et al. Immune responses following mouse peripheral nerve xenotransplantation in rats[J]. J Biomed Biotechnol， 2009， 2009：412598.
49.	Yu X， Jiang Y， Lu L， et al. A crucial role of IL-17 and IFN-γ during acute rejection of peripheral nerve xenotransplantation in mice[J]. PLoS One， 2012， 7(3)：e34419.

1. United Network for Organ Sharing. Transplant trends[EB/OL]. 2013-3-10. http：//www. unos. org/.
2. Eurotransplant. Annual report 2012[EB/OL]. 2013-1-1. http：//www. eurotransplant. org/.
3. Sandrin MS， Vaughan HA， Dabkowski PL， et al. Anti-pig IgM antibodies in human serum react predominantly with Gal （alpha 1-3) Gal epitopes[J]. Proc Natl Acad Sci U S A， 1993， 90(23)：11391-11395.
4. Macher BA， Galili U. The galalpha1， 3galbeta1， 4GlcNAc-R(alpha-Gal) epitope：a carbohydrate of unique evolution and clinicalrelevance[J]. Biochim Biophys Acta， 2008， 1780(2)：75-88.
5. Lai L， Kolber-Simonds D， Park KW， et al. Production of alpha-1，3-galactosyltransferase knockout pigs by nuclear transfer cloning[J]. Science， 2002， 295(5557)：1089-1092.
6. Dai Y， Vaught TD， Boone J， et al. Targeted disruption of the alpha1， 3-galactosyltransferase gene in cloned pigs[J]. Nat Biotechnol， 2002， 20(3)：251-255.
7. Phelps CJ， Koike C， Vaught TD， et al. Production of alpha 1， 3-galactosyltransferase-deficient pigs[J]. Science， 2003， 299(5605)：411-414.
8. 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.
9. Cooper DK， Bottino R， Satyananda V， et al. Toward clinical islet xenotransplantation—are revisions to the IXA guidelines warranted?[J]. Xenotransplantation， 2013， 20(2)：68-74.
10. Yeh P， Ezzelarab M， Bovin N， et al. Investigation of potential carbohydrate antigen targets for human and baboon antibodies[J]. Xenotransplantation， 2010， 17(3)：197-206.
11. Zhu B， Tong C， Guo W， et al. Synergistic suppression of pre-per-fusion of donor livers with recipient serum and cobra venom factortreatment on hyperacute rejection following liver xenotransplan-tation[J]. Acta Cir Bras， 2012， 27(5)：301-305.
12. Salerno CT， Kulick DM， Yeh CG， et al. A soluble chimeric inhibitor of C3 and C5 convertases， complement activation blocker-2， prolongs graft survival in pig-to-rhesus monkey heart transplantation[J]. Xenotransplantation， 2002， 9(2)：125-134.
13. Poirier N， Blancho G. Recombinant human C1-inhibitor inhibits cytotoxicity induced by allo- and xenoantibodies[J]. Transplant Proc， 2008， 40(2)：581-583.
14. Cowan PJ， Aminian A， Barlow H， et al. Renal xenografts from triple-transgenic pigs are not hyperacutely rejected but cause coagu-lopathy in non-immunosuppressed baboons[J]. Transplantation，2000， 69(12)：2504-2515.
15. Auchincloss H Jr， Sachs DH. Xenogeneic transplantation[J]. Annu Rev Immunol， 1998， 16：433-470.
16. Breimer ME. Gal/non-Gal antigens in pig tissues and human non-Gal antibodies in the GalT-KO era[J]. Xenotransplantation， 2011， 18(4)：215-228.
17. Chen G， Qian H， Starzl T， et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockoutpig kidneys[J]. Nat Med， 2005， 11(12)：1295-1298.
18. Horvath-Arcidiacono JA， Porter CM， Bloom ET， et al. Human NK cells can lyse porcine endothelial cells independent of their expression of Galalpha(1，3)-Gal and killing is enhanced by activation of either effector or target cells[J]. Xenotransplantation， 2006， 13(4)：318-327.
19. Ibrahim Z， Busch J， Awwad M， et al. Selected physiologic compatibilities and incompatibilities between human and porcine organ systems[J]. Xenotransplantation， 2006， 13(6)：488-499.
20. Patience C， Takeuchi Y， Weiss RA. Infection of human cells by an endogenous retrovirus of pigs[J]. Nat Med， 1997， 3(3)：282-286.
21. van der Laan LJ， Lockey C， Griffeth BC， et al. Infection by por-cine endogenous retrovirus after islet xenotransplantation in SCID mice[J]. Nature， 2000， 407(6800)：90-94.
22. Paradis K， Langford G， Long Z， et al. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group[J]. Science， 1999， 285(5431)：1236-1241.
23. Hector RD， Meikle S， Grant L， et al. Pre-screening of miniature swine may reduce the risk of transmitting human tropic recombinant porcine endogenous retroviruses[J]. Xenotransplantation， 2007， 14(3)：222-226.
24. Ekser B， Ezzelarab M， Hara H， et al. Clinical xenotransplantation：the next medical revolution?[J]. Lancet， 2012， 379(9816)：672-683.
25. Marigliano M， Bertera S， Grupillo M， et al. Pig-to-nonhuman primates pancreatic islet xenotransplantation：an overview[J]. Curr Diab Rep， 2011， 11(5)：402-412.
26. van der Windt DJ， Bottino R， Kumar G， et al. Clinical islet xenotransplantation：how close are we?[J]. Diabetes， 2012， 61(12)：3046-3055.
27. van der Windt DJ， Bottino R， Casu A， et al. Long-term controllednormoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets[J]. Am J Transplant， 2009， 9(12)：2716-2726.
28. Dufrane D， Goebbels RM， Gianello P. Alginate macroencapsul-ation of pig islets allows correction of streptozotocin-induceddiabetes in primates up to 6 months without immunosuppression[J]. Transplantation， 2010， 90(10)：1054-1062.
29. Luan NM， Iwata H. Xenotransplantation of islets enclosed in agarose microcapsule carrying soluble complement receptor 1[J]. Biomaterials， 2012， 33(32)：8075-8081.
30. Shimizu A， Hisashi Y， Kuwaki K， et al. Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1， 3-galactosyltransferase gene-knockout pigs in baboons[J]. Am J Pathol， 2008， 172(6)：1471-1481.
31. Mohiuddin MM， Corcoran PC， Singh AK， et al. B-cell depletion extends the survival of GTKO. hCD46Tg pig heart xenografts in baboons for up to 8 months[J]. Am J Transplant， 2012， 12(3)：763-771.
32. Calne RY， White HJ， Herbertson BM， et al. Pig-to-baboon liver xenografts[J]. Lancet， 1968， 1(7553)：1176-1178.
33. Ramirez P， Chavez R， Majado M， et al. 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[J]. Transplantation， 2000， 70(7)：989-998.
34. Ramirez P， Montoya MJ， Ríos A， 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)[J]. Transplant Proc， 2005， 37(9)：4103-4106.
35. Ekser B， Echeverri GJ， Hassett AC， et al. Hepatic function after genetically engineered pig liver transplantation in baboons[J]. Transplantation， 2010， 90(5)：483-493.
36. Ekser B， Long C， Echeverri GJ， et al. Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants：clinical relevance[J]. Am J Transplant， 2010， 10(2)：273-285.
37. Kim K， Schuetz C， Elias N， et al. Up to 9-day survival and controlof thrombocytopenia following alpha1， 3-galactosyl transferase knockout swine liver xenotransplantation in baboons[J]. Xenotr-ansplantation， 2012， 19(4)：256-264.
38. Baldan N， Rigotti P， Calabrese F， et al. Ureteral stenosis in HDAF pig-to-primate renal xenotransplantation：a phenomenon related to immunological events?[J]. Am J Transplant， 2004， 4(4)：475-481.
39. 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.
40. Le Bas-Bernardet S， Tillou X， Poirier N， et al. Xenotransplantation of galactosyl-transferase knockout， CD55， CD59， CD39， and fucosyl-transferase transgenic pig kidneys into baboons[J]. Transplant Proc， 2011， 43(9)：3426-3430.
41. Yedidag EN， Fryer JP， Levi E， et al. Early histopathology of small intestinal discordant xenografts[J]. Transplantation， 1996， 62(10)：1385-1391.
42. Kiyochi H， Kellersmann R， Blömer A， et al. Rat-to-mouse small bowel xenotransplantation：a novel model for studying acute vascular and hyperacute xenograft rejection and xenogenic cell migration[J]. Xenotransplantation， 1999， 6(1)：28-35.
43. Lau CL， Cantu E 3rd， Gonzalez-Stawinski GV， et al. The role of antibodies and von Willebrand factor in discordant pulmonary xenotransplantation[J]. Am J Transplant， 2003， 3(9)：1065-1075.
44. Kim YT， Lee HJ， Lee SW， et al. Pre-treatment of porcine pulm-onary xenograft with desmopressin：a novel strategy to attenuate platelet activation and systemic intravascular coagulation in an ex-vivo model of swine-to-human pulmonary xenotransplantation[J]. Xenotransplantation， 2008， 15(1)：27-35.
45. Cantu E， Balsara KR， Li B， et al. Prolonged function of macro-phage， von Willebrand factor-deficient porcine pulmonary xenografts[J]. Am J Transplant， 2007， 7(1)：66-75.
46. Sinis N， Haerle M， Becker ST， et al. Neuroma formation in a rat median nerve model：influence of distal stump and muscular coating[J]. Plast Reconstr Surg， 2007， 119(3)：960-966.
47. Galeano M， Manasseri B， Risitano G， et al. A free vein graft cap influences neuroma formation after nerve transection[J]. Microsurgery， 2009， 29(7)：568-572.
48. Lu LJ， Sun JB， Liu ZG， et al. Immune responses following mouse peripheral nerve xenotransplantation in rats[J]. J Biomed Biotechnol， 2009， 2009：412598.
49. Yu X， Jiang Y， Lu L， et al. A crucial role of IL-17 and IFN-γ during acute rejection of peripheral nerve xenotransplantation in mice[J]. PLoS One， 2012， 7(3)：e34419.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research Progress of Xenotransplantation

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