title: Science of composite tissue allotransplantation.
abstract: The science of composite tissue allotransplantation (CTA) is rooted in progressive thinking by surgeons, fueled by innovative solutions, and aided by understanding the immunology of tolerance and rejection. These three factors have allowed CTA to progress from science fiction to science fact. Research using preclinical animal models has allowed an understanding of the antigenicity of complex tissue transplants and mechanisms to promote graft acceptance. As a result, translation to the clinic has shown that CTA is a viable treatment option well on the way of becoming a standard of care for those who have lost extremities and suffered large tissue defects. The field of CTA has been progressing exponentially over the past decade. Transplantation of hands, larynx, vascularized knee, trachea, face, and abdominal wall has been performed. Several important observations have emerged from translation to the clinic. Although it was predicted that rejection would pose a major limitation, this has not proven true. In fact, steroid-sparing protocols for immunosuppression that have been successfully used in renal transplantation are sufficient to prevent rejection of limbs. Although skin is highly antigenic when transplanted alone in animal models, when part of a CTA, it has not proven to be. Chronic rejection has not been conclusively demonstrated in hand transplant recipients and is difficult to induce in rodent models of CTA. This review focuses on the science of CTA, provides a snapshot of where we are in the clinic, and discusses prospects for the future to make the procedures even more widely available.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202-1760, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Swearingen
authors.forename: Kadiyala
authors.initials: K
authors.lastname: Ravindra
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Shengli
authors.initials: S
authors.lastname: Wu
authors.forename: Warren C
authors.initials: WC
authors.lastname: Breidenbach
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000503:physiopathology; D063987:Hand Transplantation; D006801:Humans; D023421:Models, Animal; D016377:Organ Transplantation / Q000706:statistics & numerical data*; D012586:Science / Q000639:trends; D016378:Tissue Transplantation / Q000706:statistics & numerical data*; D023001:Transplantation Tolerance / Q000502:physiology; D014184:Transplantation, Homologous
references.citation: Microsurgery. 2000;20(8):360-71
references.pmid: 11150985
references.citation: Transplantation. 2003 Dec 15;76(11):1548-55
references.pmid: 14702522
references.citation: Transplantation. 2003 Aug 27;76(4):688-93
references.pmid: 12973110
references.citation: Chir Narzadow Ruchu Ortop Pol. 2007 Jul-Aug;72(4):279-82
references.pmid: 18078283
references.citation: Transplantation. 2001 Apr 15;71(7):851-6
references.pmid: 11349715
references.citation: Transplantation. 2005 Aug 27;80(4):457-65
references.pmid: 16123718
references.citation: Transplant Proc. 2007 Sep;39(7):2076-8
references.pmid: 17889100
references.citation: Am J Transplant. 2006 Jan;6(1):20-6
references.pmid: 16433752
references.citation: Clin Transplant. 2003 Oct;17(5):455-60
references.pmid: 14703930
references.citation: Microsurgery. 2000;20(8):458-65
references.pmid: 11151000
references.citation: Microsurgery. 2007;27(7):630-6
references.pmid: 17868137
references.citation: N Engl J Med. 2001 May 31;344(22):1676-9
references.pmid: 11386266
references.citation: J Immunol. 2008 Jan 1;180(1):49-57
references.pmid: 18097003
references.citation: Lancet. 1999 Apr 17;353(9161):1315-20
references.pmid: 10218530
references.citation: Drug Saf. 2000 Aug;23(2):101-13
references.pmid: 10945373
references.citation: Plast Reconstr Surg. 1991 Mar;87(3):401-11
references.pmid: 1998012
references.citation: Transplantation. 2005 May 15;79(9):1210-4
references.pmid: 15880072
references.citation: Ann Surg. 2004 Sep;240(3):510-6; discussion 516-7
references.pmid: 15319722
references.citation: Transplantation. 2006 Feb 15;81(3):418-22
references.pmid: 16477229
references.citation: Immunol Rev. 2006 Aug;212:8-27
references.pmid: 16903903
references.citation: N Engl J Med. 2007 Dec 13;357(24):2451-60
references.pmid: 18077810
references.citation: J Trauma. 1980 May;20(5):390-8
references.pmid: 7365852
references.citation: Transplantation. 1968 Jul;6(4):619
references.pmid: 4876502
references.citation: Br J Plast Surg. 2004 Jul;57(5):381-91
references.pmid: 15191817
references.citation: Arch Orthop Trauma Surg. 1997;116(3):125-8
references.pmid: 9061165
references.citation: Br J Plast Surg. 1973 Jul;26(3):194-201
references.pmid: 4726099
references.citation: Am J Surg. 1998 Nov;176(5):418-21
references.pmid: 9874425
references.citation: Immunol Rev. 2003 Dec;196:125-46
references.pmid: 14617202
references.citation: Transplantation. 1996 Feb 27;61(4):527-32
references.pmid: 8610375
references.citation: Transplantation. 1966 Sep;4(5):605-17
references.pmid: 5339407
references.citation: J Hand Surg Am. 2002 Sep;27(5):760-70
references.pmid: 12239664
references.citation: Transplant Proc. 1998 Sep;30(6):2746-53
references.pmid: 9745560
references.citation: Transplantation. 2006 Dec 27;82(12):1764-8
references.pmid: 17198273
references.citation: Handchir Mikrochir Plast Chir. 2002 Mar;34(2):75-83
references.pmid: 12073182
references.citation: Plast Reconstr Surg. 1992 Jun;89(6):1135-47
references.pmid: 1584877
references.citation: Ann Surg. 2003 Jul;238(1):128-36
references.pmid: 12832975
references.citation: Ann Plast Surg. 1984 Mar;12(3):249-55
references.pmid: 6609665
references.citation: J Exp Med. 2005 Feb 7;201(3):373-83
references.pmid: 15699072
references.citation: Science. 1992 Aug 7;257(5071):789-92
references.pmid: 1323143
references.citation: Am J Transplant. 2005 Feb;5(2):228-36
references.pmid: 15643982
references.citation: Am J Transplant. 2008 Mar;8(3):688-96
references.pmid: 18261182
references.citation: Curr Top Microbiol Immunol. 2006;305:51-66
references.pmid: 16724800
references.citation: Transpl Immunol. 2007 Jul;18(1):1-6
references.pmid: 17584595
references.citation: Transplantation. 2004 Feb 27;77(4):514-21
references.pmid: 15084927
references.citation: Plast Reconstr Surg. 1973 Nov;52(5):476-89
references.pmid: 4583285
references.citation: Lancet. 2004 May 22;363(9422):1663
references.pmid: 15158625
references.citation: Crit Care Clin. 1990 Oct;6(4):955-77
references.pmid: 2265389
references.citation: J Exp Med. 2000 Nov 6;192(9):1213-22
references.pmid: 11067871
references.citation: Eur Urol. 2006 Oct;50(4):851-3
references.pmid: 16930814
references.citation: Transplant Proc. 1988 Feb;20(1 Suppl 1):1061-7
references.pmid: 3279601
references.citation: J Immunol. 2007 Aug 15;179(4):2153-62
references.pmid: 17675474
references.citation: Microsurgery. 2005;25(5):410-4
references.pmid: 16037937
references.citation: Lancet. 1998 Feb 21;351(9102):539-40
references.pmid: 9492768
references.citation: Otolaryngol Head Neck Surg. 2004 Dec;131(6):1016-8
references.pmid: 15577810
references.citation: Transpl Int. 2007 May;20(5):410-8
references.pmid: 17274795
references.citation: Chin J Traumatol. 2003 Oct;6(5):284-7
references.pmid: 14514365
references.citation: Transplantation. 2003 Feb 15;75(3):275-81
references.pmid: 12589145
references.citation: J Hand Surg Br. 2002 Aug;27(4):385-90
references.pmid: 12162985
references.citation: Bull Menninger Clin. 1999 Winter;63(1):13-39
references.pmid: 10028744
references.citation: J Immunol. 2006 Oct 1;177(7):4488-94
references.pmid: 16982885
references.citation: Annu Rev Immunol. 2005;23:975-1028
references.pmid: 15771591
references.citation: Transplantation. 2000 Mar 15;69(5):743-9
references.pmid: 10755520
references.citation: J Immunol. 2017 Feb 1;198(3):981-985
references.pmid: 28115586
references.citation: Surgery. 1999 Aug;126(2):384-8
references.pmid: 10455910
references.citation: Nature. 1984 Jan 12-18;307(5947):168-70
references.pmid: 6361574
references.citation: J Immunol. 2007 Jun 1;178(11):7018-31
references.pmid: 17513751
references.citation: Transplant Proc. 1997 Feb-Mar;29(1-2):344-7
references.pmid: 9123032
references.citation: Transplantation. 2003 Sep 27;76(6):988-94
references.pmid: 14508367
references.citation: J Hand Surg Eur Vol. 2007 Feb;32(1):2-17
references.pmid: 17084950
references.citation: Transplant Proc. 1998 Sep;30(6):2743-5
references.pmid: 9745559
references.citation: Transplantation. 1999 Feb 27;67(4):520-5
references.pmid: 10071020
references.citation: Plast Reconstr Surg. 1971 May;47(5):425-31
references.pmid: 4930001
references.citation: N Engl J Med. 2000 Aug 17;343(7):468-73
references.pmid: 10950668
references.citation: J Heart Lung Transplant. 1998 Aug;17(8):801-8
references.pmid: 9730430
references.citation: Transplantation. 2003 Apr 15;75(7):922-32
references.pmid: 12698075
references.citation: Transplantation. 1991 Sep;52(3):389-98
references.pmid: 1680253
references.citation: Transplantation. 2001 Jul 15;72(1):122-6
references.pmid: 11468546
references.citation: Plast Reconstr Surg. 1992 Oct;90(4):695-9
references.pmid: 1410009
references.citation: Transplantation. 2002 Jul 15;74(1):85-90
references.pmid: 12134104
references.citation: Transplantation. 1998 Dec 27;66(12):1581-7
references.pmid: 9884243
references.citation: JAMA. 1989 Mar 10;261(10):1483-4
references.pmid: 2918643
references.citation: Transpl Int. 2000;13 Suppl 1:S521-4
references.pmid: 11112064
references.citation: Transplant Proc. 2005 Mar;37(2):1392-5
references.pmid: 15848730
references.citation: Transplant Proc. 1991 Feb;23(1 Pt 1):623-5
references.pmid: 1990628
references.citation: Ann N Y Acad Sci. 1962 Oct 24;99:743-61
references.pmid: 14017936
references.citation: N Engl J Med. 2005 Dec 1;353(22):2342-51
references.pmid: 16319383
references.citation: Transplantation. 1993 Apr;55(4):752-6; discussion 756-7
references.pmid: 8475548
references.citation: Plast Reconstr Surg. 2004 Dec;114(7):1790-801
references.pmid: 15577350
references.citation: Microsurgery. 2000;20(8):453-7
references.pmid: 11150999
references.citation: Clin Plast Surg. 2007 Apr;34(2):271-8, ix-x
references.pmid: 17418676
references.citation: Plast Reconstr Surg. 1965 Jul;36:62-70
references.pmid: 14310548
references.citation: Lancet. 2003 Jun 28;361(9376):2173-6
references.pmid: 12842369
references.citation: Plast Reconstr Surg. 1973 Nov;52(5):490-502
references.pmid: 4583286
references.citation: Microsurgery. 2006;26(8):566-72
references.pmid: 17091477
references.citation: Transplantation. 2006 May 27;81(10):1435-41
references.pmid: 16732182
references.citation: J Hand Surg Br. 2006 Aug;31(4):371-6
references.pmid: 16527381
references.citation: JAMA. 1989 Jun 23-30;261(24):3561-6
references.pmid: 2542633
references.citation: Circulation. 1998 Nov 10;98(19 Suppl):II163-8; discussion II168-9
references.pmid: 9852899
references.citation: Am J Transplant. 2007 Jul;7(7):1753-62
references.pmid: 17511764
references.citation: J Am Coll Dent. 2014 Summer;81(3):4-13
references.pmid: 25951677
references.citation: Zhonghua Yi Xue Za Zhi. 2000 Jun;80(6):417-21
references.pmid: 11798796
references.citation: Nat Rev Immunol. 2007 Aug;7(8):610-21
references.pmid: 17627284
references.citation: Blood. 2002 May 15;99(10):3493-9
references.pmid: 11986199
references.citation: Transplantation. 2005 Nov 27;80(10):1447-54
references.pmid: 16340790
references.citation: Microsurgery. 2000;20(3):143-9
references.pmid: 10790178
references.citation: Transplant Proc. 2004 Jun;36(5):1561-3
references.pmid: 15251385
references.citation: Transplantation. 1995 Feb 27;59(4):565-72
references.pmid: 7878762
references.citation: Transplantation. 2003 Jan 15;75(1):25-31
references.pmid: 12544866