異種移植的研究進展_《中國普外基礎與臨床雜志》

作者：

姚丹華 ,  李幼生 , 黎介壽

南京大學醫學院臨床學院，南京軍區南京總醫院普通外科研究所（江蘇南京 210002）;

關鍵詞：

異種移植超急性異種排斥反應轉基因基因敲除

視頻：

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摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

目的　總結異種移植的研究現狀與進展。
方法　復習國內外關于異種移植研究的相關文獻并進行綜述。
結果　超急性異種排斥反應是異種移植面臨的巨大問題，器官或組織的供體經過基因修飾后，在一定程度上可以減輕超急性異種排斥反應。由于不同的器官具有不同的特性，目前異種器官移植移植物的存活時間存在較大差異。
結論　通過對相關異種移植實驗研究的分析，可以全面地了解異種移植的研究背景，為異種移植提供合適的研究方向。將經基因修飾的動物作為異種器官或組織的供體，有望使移植物避免或減輕超急性異種排斥反應。

引用本文： 姚丹華,李幼生,黎介壽. 異種移植的研究進展. 中國普外基礎與臨床雜志, 2013, 20(12): 1437-1441. doi: 復制

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.

《中國普外基礎與臨床雜志》

異種移植的研究進展

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

《中國普外基礎與臨床雜志》

異種移植的研究進展

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

摘要全文圖表視頻參考文獻施引文獻補充材料