Overcoming the barriers to xenotransplantation: prospects for the future.
Cross-species transplantation (xenotransplantation) has immense potential to solve the critical need for organs, tissues and cells for clinical transplantation. The increasing availability of genetically engineered pigs is enabling progress to be made in pig-to-nonhuman primate experimental models. Potent pharmacologic immunosuppressive regimens have largely prevented T-cell rejection and a T-cell-dependent elicited antibody response. However, coagulation dysfunction between the pig and primate is proving to be a major problem, and this can result in life-threatening consumptive coagulopathy. This complication is unlikely to be overcome until pigs expressing a human 'antithrombotic' or 'anticoagulant' gene, such as thrombomodulin, tissue factor pathway inhibitor or CD39, become available. Progress in islet xenotransplantation has been more encouraging, and diabetes has been controlled in nonhuman primates for periods in excess of 6 months, although this has usually been achieved using immunosuppressive protocols that might not be clinically applicable. Further advances are required to overcome the remaining barriers.
Ekser
Burcin
B
Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Cooper
David K C
DK
D000818:Animals; D030801:Animals, Genetically Modified; D001778:Blood Coagulation Disorders / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D003920:Diabetes Mellitus / Q000628:therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology; D011323:Primates; D013552:Swine; D018180:Thrombomodulin / Q000235:genetics / Q000276:immunology; D014183:Transplantation, Heterologous / Q000639:trends*
D007166:Immunosuppressive Agents; D008074:Lipoproteins; C546931:THBD protein, human; D018180:Thrombomodulin; C051928:lipoprotein-associated coagulation inhibitor
Lancet. 1998 Aug 29;352(9129):699-701
9728987
Transplantation. 2000 Oct 15;70(7):989-98
11045632
Xenotransplantation. 2006 Sep;13(5):400-7
16925663
Eur J Immunol. 2000 Feb;30(2):586-93
10671215
J Biol Chem. 1988 Nov 25;263(33):17755-62
2460463
Nat Med. 2004 Nov;10(11):1227-33
15502841
Am J Transplant. 2002 Jul;2(6):520-5
12118895
Transplantation. 2000 Nov 15;70(9):1323-31
11087147
Transplantation. 2000 Jul 15;70(1):15-21
10919569
Transplantation. 1997 Jan 15;63(1):149-55
9000677
J Clin Invest. 2004 May;113(10):1440-6
15146241
Xenotransplantation. 2004 Mar;11(2):171-83
14962279
Transpl Immunol. 2009 Jun;21(2):75-80
19000927
N Engl J Med. 2001 Mar 15;344(11):793-800
11248154
Transplant Proc. 1999 Feb-Mar;31(1-2):958
10083425
Proc Natl Acad Sci U S A. 2004 May 11;101(19):7335-40
15123792
Transplantation. 2004 Jun 15;77(11):1735-41
15201675
Transplantation. 1998 Jun 27;65(12):1584-90
9665074
Xenotransplantation. 2003 Jul;10(4):300-10
12795679
Xenotransplantation. 2006 Nov;13(6):488-99
17059572
Xenotransplantation. 2005 Jul;12(4):258-65
15943774
Xenotransplantation. 2008 Feb;15(1):36-45
18333912
Xenotransplantation. 2007 Jul;14(4):288-97
17669170
Transplantation. 2006 Dec 27;82(12):1787-91
17198277
Transplantation. 1996 Mar 27;61(6):862-8
8623150
Transpl Immunol. 1993;1(3):198-205
7521740
Transplantation. 2009 Nov 15;88(9):1041-9
19898198
J Heart Lung Transplant. 2000 Feb;19(2):224-9
10703701
Xenotransplantation. 2005 May;12(3):168-72
15807765
Am J Transplant. 2004 Dec;4(12):1958-63
15575897
Xenotransplantation. 2004 May;11(3):237-46
15099203
Transplantation. 2002 Jun 15;73(11):1717-23
12084992
Immunol Cell Biol. 2005 Aug;83(4):396-404
16033535
Trans Assoc Am Physicians. 1991;104:164-72
1726964
Transplantation. 2003 May 27;75(10):1615-24
12777846
Xenotransplantation. 2009 Nov-Dec;16(6):477-85
20042047
Xenotransplantation. 1998 Nov;5(4):234-45
9915251
Transplantation. 2007 Jan 27;83(2):193-201
17264816
Xenotransplantation. 2009 May-Jun;16(3):164-80
19566656
Transplantation. 2000 Jun 15;69(11):2296-304
10868629
Kidney Int. 2001 Oct;60(4):1592-7
11576378
Transpl Int. 2006 Feb;19(2):158-65
16441365
Am J Transplant. 2009 Dec;9(12):2716-26
19845582
Xenotransplantation. 2006 Jul;13(4):357-65
16768729
J Immunol. 1997 Oct 1;159(7):3655-61
9317166
Transplantation. 2008 Sep 15;86(5):702-9
18791452
Trends Immunol. 2005 Jan;26(1):2-5
15629401
Nat Med. 2005 Jan;11(1):29-31
15619628
Transpl Int. 2007 Dec;20(12):1050-8
17850234
J Am Soc Nephrol. 2005 Sep;16(9):2732-45
16049072
Transplantation. 1999 Aug 27;68(4):480-4
10480403
Transplantation. 2005 Aug 15;80(3):344-52
16082330
Clin Transplant. 1992 Jun;6(3 part 1):178-83
10147930
Xenotransplantation. 2000 Aug;7(3):181-5
11021663
Xenotransplantation. 2005 Jan;12(1):13-9
15598269
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12045-50
14523234
Transplantation. 2003 Jun 15;75(11):1841-7
12811243
Transpl Immunol. 1994 Jun;2(2):81-6
7953322
Xenotransplantation. 2000 May;7(2):143-55
10961299
Transplantation. 2004 Dec 27;78(12):1721-8
15614144
Xenotransplantation. 2008 Mar-Apr;15(2):116-20
18447884
Transplantation. 2004 Jan 15;77(1):1-5
14724427
Transplantation. 1994 Aug 15;58(3):330-7
8053057
Am J Transplant. 2010 Feb;10(2):273-85
20041862
Xenotransplantation. 2004 Sep;11(5):416-25
15303978
Xenotransplantation. 1998 Feb;5(1):6-17
9507728
Am J Transplant. 2005 Sep;5(9):2085-93
16095487
Xenotransplantation. 2008 Jul-Aug;15(4):225-34
18957045
Clin Exp Pharmacol Physiol. 1999 Dec;26(12):1016-9
10626074
Curr Opin Organ Transplant. 2008 Apr;13(2):178-83
18685300
J Immunol. 2004 May 15;172(10):6460-7
15128838
Xenotransplantation. 2000 Feb;7(1):31-41
10809055
Am J Pathol. 2008 Jun;172(6):1471-81
18467706
J Heart Lung Transplant. 1991 Mar-Apr;10(2):223-34
2031919
Science. 2003 Jan 17;299(5605):411-4
12493821
Xenotransplantation. 2004 Jan;11(1):101-6
14962299
Transplantation. 2009 Jan 15;87(1):35-43
19136889
Xenotransplantation. 2002 Nov;9(6):376-81
12371933
Science. 1999 Aug 20;285(5431):1236-41
10455044
J Immunol. 1998 Nov 15;161(10):5116-9
9820477
J Heart Transplant. 1988 May-Jun;7(3):238-46
3290407
Ann R Coll Surg Engl. 1997 Jan;79(1):13-9
9038490
Xenotransplantation. 2004 May;11(3):247-53
15099204
J Immunol. 2001 Feb 1;166(3):2133-40
11160265
Nat Rev Immunol. 2007 Jul;7(7):519-31
17571072
Transplantation. 1993 Dec;56(6):1433-42
8279016
Transplantation. 2007 Jul 15;84(1):1-7
17627227
Transplantation. 2006 Aug 15;82(3):314-9
16906027
J Heart Transplant. 1986 Nov-Dec;5(6):411-8
3302173
Immunol Rev. 1994 Oct;141:5-30
7868157
Transplantation. 2009 Mar 27;87(6):805-12
19300181
J Heart Lung Transplant. 1996 Aug;15(8):804-17
8878763
Transplantation. 1998 Jan 27;65(2):172-9
9458010
Nat Med. 1995 Sep;1(9):964-6
7585226
Annu Rev Med. 2002;53:133-47
11818467
J Leukoc Biol. 2005 Jul;78(1):51-61
15809289
Transplantation. 1997 Nov 15;64(9):1255-61
9371665
Mol Immunol. 2005 Jun;42(10):1205-14
15829309
Xenotransplantation. 2005 Mar;12(2):85-7
15693838
Curr Drug Targets Cardiovasc Haematol Disord. 2005 Jun;5(3):255-69
15975038
Transplantation. 2007 Jan 27;83(2):202-10
17264817
Lancet. 1993 Sep 11;342(8872):682-3
8103167
Am J Transplant. 2004 Mar;4(3):363-72
14961988
Transplantation. 2001 Dec 15;72(11):1743-52
11740383
Transplantation. 1996 Nov 27;62(10):1379-84
8958260
J Heart Lung Transplant. 2007 Mar;26(3):210-8
17346622
Nat Med. 2006 Mar;12(3):301-3
16491083
J Immunol. 2001 Nov 15;167(10):6002-8
11698480
Am J Phys Anthropol. 2001;Suppl 33:54-69
11786991
J Thorac Cardiovasc Surg. 2005 Sep;130(3):844-51
16153938
Transplantation. 2005 Nov 27;80(10):1493-500
16340796
Nat Med. 2006 Mar;12(3):304-6
16501570
Transplantation. 1999 Jan 15;67(1):18-30
9921791
J Immunol. 1995 Dec 1;155(11):5249-56
7594537
Transplantation. 2004 Dec 15;78(11):1569-75
15591943
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5062-6
17360380
Transplantation. 2008 Nov 27;86(10):1452-62
19034017
Diabetes. 2005 Apr;54(4):1048-55
15793243
J Thorac Cardiovasc Surg. 2007 May;133(5):1354-63
17467457
Transfusion. 2009 Nov;49(11):2418-29
19624491
Transplantation. 2005 Jan 15;79(1):1-9
15714161
Transplantation. 1997 Mar 15;63(5):749-58
9075849
Xenotransplantation. 2005 May;12(3):181-8
15807768
Transplant Proc. 1997 Feb-Mar;29(1-2):884-5
9123568
Transplant Proc. 1992 Apr;24(2):559-62
1566430
Ann Transplant. 2001;6(3):12-6
11899892
Transplantation. 1991 Sep;52(3):530-3
1716798
Transplantation. 2006 Jan 27;81(2):273-83
16436972
Am J Transplant. 2004 Sep;4(9):1383-90
15307825
Transplantation. 1999 Mar 27;67(6):784-91
10199724
Liver Transpl. 2008 Apr;14(4):425-34
18383106
Transplantation. 1998 Feb 15;65(3):346-53
9484750
Glycoconj J. 1996 Dec;13(6):947-53
8981086
Transplantation. 1994 Nov 27;58(10):1059-66
7974711
Nat Med. 2005 Jan;11(1):32-4
15619627
Transplantation. 1997 May 15;63(9):1318-30
9158028
Blood. 1997 Dec 1;90(11):4425-37
9373253
Transpl Int. 2008 Dec;21(12):1163-74
18764834
Hum Immunol. 2000 Nov;61(11):1066-73
11137209
Hum Immunol. 1997 Dec;58(2):91-105
9475338
Xenotransplantation. 2000 Aug;7(3):166-76
11021661
Transplantation. 1995 Jan 27;59(2):256-62
7839449
Transplantation. 2005 May 27;79(10):1324-31
15912099
Xenotransplantation. 2009 May-Jun;16(3):121-8
19566651