title: Induction of cardiac allograft tolerance across a full MHC barrier in miniature swine by donor kidney cotransplantation.
abstract: We have previously shown that tolerance of kidney allografts across a full major histocompatibility complex (MHC) barrier can be induced in miniature swine by a 12-day course of high-dose tacrolimus. However, that treatment did not prolong survival of heart allografts across the same barrier. We have now tested the effect of cotransplanting an allogeneic heart and kidney from the same MHC-mismatched donor using the same treatment regimen. Heart allografts (n = 3) or heart plus kidney allografts (n = 5) were transplanted into MHC-mismatched recipients treated with high-dose tacrolimus for 12 days. As expected, all isolated heart allografts rejected by postoperative day 40. In contrast, heart and kidney allografts survived for >200 days with no evidence of rejection on serial cardiac biopsies. Heart/kidney recipients lost donor-specific responsiveness in cell-mediated lympholysis and mixed-lymphocyte reaction assays, were free of alloantibody and exhibited prolonged survival of donor, but not third-party skin grafts. Late (>100 days) removal of the kidney allografts did not cause acute rejection of the heart allografts (n = 2) and did not abrogate donor-specific unresponsiveness in vitro. While kidney-induced cardiac allograft tolerance (KICAT) has previously been demonstrated across a Class I disparity, these data demonstrate that this phenomenon can also be observed across the more clinically relevant full MHC mismatch. Elucidating the renal element(s) responsible for KICAT could provide mechanistic information relevant to the induction of tolerance in recipients of isolated heart allografts as well as other tolerance-resistant organs.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: M L
authors.initials: ML
authors.lastname: Madariaga
authors.forename: S G
authors.initials: SG
authors.lastname: Michel
authors.forename: M
authors.initials: M
authors.lastname: Tasaki
authors.forename: V
authors.initials: V
authors.lastname: Villani
authors.forename: G M
authors.initials: GM
authors.lastname: La Muraglia
authors.forename: S
authors.initials: S
authors.lastname: Sihag
authors.forename: J
authors.initials: J
authors.lastname: Gottschall
authors.forename: E A
authors.initials: EA
authors.lastname: Farkash
authors.forename: A
authors.initials: A
authors.lastname: Shimizu
authors.forename: J S
authors.initials: JS
authors.lastname: Allan
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: J C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D064591:Allografts; D000818:Animals; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D016038:Skin Transplantation; D013552:Swine; D013556:Swine, Miniature; D014019:Tissue Donors; D023001:Transplantation Tolerance
chemical_list: D007166:Immunosuppressive Agents
keywords: Heart transplantation; kidney transplantation; miniature swine; tolerance
references.citation: Nephrol Dial Transplant. 2004 Nov;19(11):2713-20
references.pmid: 15353579
references.citation: Am J Pathol. 2007 Dec;171(6):1915-22
references.pmid: 17991712
references.citation: Transplantation. 2001 Jan 27;71(2):306-13
references.pmid: 11213078
references.citation: Kidney Int. 1993 Nov;44(5):927-31
references.pmid: 8264151
references.citation: Am J Transplant. 2008 Apr;8(4):753-60
references.pmid: 18294345
references.citation: Hepatology. 2011 Mar;53(3):1007-19
references.pmid: 21374665
references.citation: Am J Transplant. 2007 Apr;7(4):914-22
references.pmid: 17286616
references.citation: Transplantation. 2003 Aug 27;76(4):625-31
references.pmid: 12973099
references.citation: Transplantation. 1979 Jul;28(1):18-23
references.pmid: 156419
references.citation: Kidney Int. 1993 Nov;44(5):1030-5
references.pmid: 8264132
references.citation: Am J Transplant. 2003 Sep;3(9):1107-15
references.pmid: 12919090
references.citation: Kidney Int. 1998 Mar;53(3):679-89
references.pmid: 9507214
references.citation: J Immunol. 2008 Mar 1;180(5):3103-12
references.pmid: 18292533
references.citation: Sci Transl Med. 2011 Nov 30;3(111):111ra120
references.pmid: 22133721
references.citation: Transplantation. 2001 May 27;71(10):1368-79
references.pmid: 11391221
references.citation: Kidney Int Suppl. 1993 Jan;39:S124-8
references.pmid: 7682262
references.citation: J Heart Lung Transplant. 2010 Jul;29(7):717-27
references.pmid: 20620917
references.citation: J Immunol. 1992 Apr 15;148(8):2324-30
references.pmid: 1560195
references.citation: Transplantation. 1976 Dec;22(6):559-67
references.pmid: 137560
references.citation: Transplantation. 1998 Feb 15;65(3):304-13
references.pmid: 9484744
references.citation: J Thorac Cardiovasc Surg. 2000 Apr;119(4 Pt 1):709-19
references.pmid: 10733759
references.citation: Am J Physiol Renal Physiol. 2007 Sep;293(3):F801-12
references.pmid: 17609291
references.citation: Nat Immunol. 2006 Jun;7(6):652-62
references.pmid: 16633346
references.citation: Am J Transplant. 2012 Feb;12(2):330-40
references.pmid: 22053723
references.citation: Nat Immunol. 2011 Jul 31;12(9):870-8
references.pmid: 21804557
references.citation: Transplantation. 1999 Aug 27;68(4):485-91
references.pmid: 10480404
references.citation: J Heart Transplant. 1988 May-Jun;7(3):176-82
references.pmid: 3290400
references.citation: Hepatology. 2009 Dec;50(6):1981-91
references.pmid: 19821484
references.citation: Lancet. 1994 Jan 8;343(8889):67-8
references.pmid: 7903772
references.citation: Transplantation. 1996 Jul 15;62(1):75-83
references.pmid: 8693550
references.citation: Transplantation. 1997 Jul 15;64(1):178-81
references.pmid: 9233724
references.citation: Kidney Int. 2006 Aug;70(3):591-6
references.pmid: 16760907
references.citation: Am J Pathol. 2011 Apr;178(4):1635-45
references.pmid: 21435448
references.citation: Am J Transplant. 2013 May;13(5):1193-202
references.pmid: 23464595
references.citation: Am J Transplant. 2005 Aug;5(8):1808-19
references.pmid: 15996227
references.citation: Transpl Immunol. 2003 Jul-Sep;11(3-4):367-74
references.pmid: 12967789
references.citation: Transplantation. 1979 Jul;28(1):24-30
references.pmid: 156420
references.citation: Transplantation. 2012 Feb 15;93(3):272-82
references.pmid: 22179405
references.citation: J Thorac Cardiovasc Surg. 1996 Jun;111(6):1230-9
references.pmid: 8642825
references.citation: Methods Mol Biol. 2011;677:127-47
references.pmid: 20941607
references.citation: J Heart Lung Transplant. 2012 Oct;31(10):1052-64
references.pmid: 22975095
references.citation: Int J Clin Exp Med. 2008;1(3):192-202
references.pmid: 19079658