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1.
Transplantation ; 68(4): 485-91, 1999 Aug 27.
Article in English | MEDLINE | ID: mdl-10480404

ABSTRACT

BACKGROUND: We have previously demonstrated that MHC class I disparate hearts transplanted into miniature swine treated with a short course of cyclosporine developed florid cardiac allograft vasculopathy (CAV) and were rejected within 55 days. However, when a donor-specific kidney is cotransplanted with the heart allograft, recipients become tolerant to donor antigen and accept both allografts long-term without the development of CAV. In the present study, we have investigated the role of the host thymus in the induction of tolerance and prevention of CAV in heart/kidney recipients. METHODS: Total thymectomies were performed in six animals (postoperative day [POD]-21), which on day 0 received either an isolated MHC class I disparate heart allograft (n=3) or combined class I disparate heart and kidney allografts (n=3), followed in both cases by a 12-day course of cyclosporine (POD 0-11). Graft survival and the development of CAV in these thymectomized recipients were compared to the same parameters in non-thymectomized, cyclosporine-treated recipients bearing either class I disparate heart allografts (n=5) or heart and kidney allografts (n=4). RESULTS: In the group of animals bearing isolated class I disparate heart allografts, the thymectomized recipients rejected their allografts earlier (POD 8, 22, 27) than the non-thymectomized recipients (POD 33,35,45,47,55). The donor hearts in both the thymectomized and non-thymectomized animals developed florid CAV. In the group of animals bearing combined class I disparate heart and kidney allografts, the nonthymectomized recipients accepted both donor organs long term with no evidence of CAV. In contrast, none of the thymectomized heart/kidney recipients survived >100 days, and they all developed the intimal proliferation of CAV. CONCLUSION: Thymic-dependent mechanisms are necessary for the induction of acquired tolerance and prevention of CAV in porcine heart/kidney recipients.


Subject(s)
Heart Transplantation/immunology , Immune Tolerance , Kidney Transplantation/immunology , Thymus Gland/immunology , Animals , Cyclosporine/administration & dosage , Heart Transplantation/adverse effects , Heart Transplantation/pathology , Histocompatibility Antigens Class I , Immunosuppressive Agents/administration & dosage , Models, Biological , Swine , Swine, Miniature , Thymectomy , Transplantation, Homologous , Vascular Diseases/etiology , Vascular Diseases/immunology , Vascular Diseases/prevention & control
3.
Transplantation ; 66(6): 810-4, 1998 Sep 27.
Article in English | MEDLINE | ID: mdl-9771848

ABSTRACT

BACKGROUND: A state of tolerance may be more easily achieved if fully vascularized and functional donor thymus is transferred to the recipient at the time of whole organ transplantation. METHODS: A composite "thymoheart" allograft was created by implanting autologous thymus into a donor heart 60-90 days before organ procurement. Successful intracardiac engraftment of autologous thymus was documented by histology and by flow cytometric analysis. RESULTS: Histology of the thymic autografts at explantation revealed viable thymus with preservation of normal thymic architecture. Cells retrieved from thymic autografts 60 days after implantation exhibited the same MHC class I and class II staining profiles by flow cytometry as cells taken from the residual native thymus. CONCLUSION: We have created a novel composite organ that confers vascularized and functional donor thymus to heart allograft recipients at the time of transplantation without affecting cardiac function.


Subject(s)
Heart Transplantation/methods , Thymus Gland/transplantation , Animals , Heart Transplantation/immunology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Swine , Swine, Miniature , Thymus Gland/cytology , Thymus Gland/immunology , Transplantation, Homologous/methods
4.
Transplantation ; 65(3): 304-13, 1998 Feb 15.
Article in English | MEDLINE | ID: mdl-9484744

ABSTRACT

BACKGROUND: The mechanisms and treatment of cardiac allograft vasculopathy (CAV) remain elusive. We have used partially inbred miniature swine to determine the role of class I MHC antigens in the pathogenesis of CAV and to determine whether acquired tolerance to donor antigen can prevent the development of CAV in large animals. METHODS: Previous studies demonstrated that miniature swine treated with 12 days of cyclosporine (CsA) after the transplantation of MHC class I-disparate kidney allografts all became tolerant to the donor kidneys and survived indefinitely. In the present study, heart allografts were transplanted across the same MHC class I disparity in CsA-treated swine. RESULTS: Unlike kidney allografts, heart allografts were rejected in 33-55 days. By postoperative day 28, all cardiac allografts had developed the intimal proliferation characteristic of CAV. When hearts and kidneys from the same donors were transplanted simultaneously into class I-disparate, CsA-treated recipients, the hosts became tolerant to their cardiac allografts and survived long-term. Furthermore, none of the hearts from the combined heart/kidney recipients developed evidence of CAV. Thus, this report demonstrates that: (1) MHC class I antigens play an important role in the pathogenesis of CAV, (2) the specific unresponsiveness to donor class I antigen induced by a class I-disparate kidney protects a heart transplanted from the same organ donor, and (3) the induction of acquired tolerance prevents the development of CAV. CONCLUSION: These findings in a preclinical system establish the significance of antigen-dependent mechanisms in the pathogenesis of CAV and underscore the importance of achieving tolerance in clinical transplantation.


Subject(s)
Coronary Disease/prevention & control , Coronary Vessels/pathology , Heart Transplantation/immunology , Heart Transplantation/pathology , Histocompatibility Antigens Class I , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/immunology , Postoperative Complications/prevention & control , Animals , Coronary Disease/pathology , Cyclosporine/therapeutic use , Graft Rejection/immunology , Graft Rejection/pathology , Histocompatibility Testing , Kidney Transplantation/pathology , Swine , Swine, Miniature , Time Factors , Transplantation, Homologous , Tunica Intima/pathology
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