The effect of thymectomy on tolerance induction and cardiac allograft vasculopathy in a miniature swine heart/kidney transplantation model.
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.


CONCLUSIONS
Thymic-dependent mechanisms are necessary for the induction of acquired tolerance and prevention of CAV in porcine heart/kidney recipients.
Yamada
K
K
Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Choo
J K
JK
Allan
J S
JS
Erhorn
A E
AE
Menard
M T
MT
Mawulawde
K
K
Slisz
J K
JK
Aretz
H T
HT
Shimizu
A
A
Sachs
D H
DH
Madsen
J C
JC
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016030:Kidney Transplantation / Q000276:immunology*; D008954:Models, Biological; D013552:Swine; D013556:Swine, Miniature; D013934:Thymectomy; D013950:Thymus Gland / Q000276:immunology*; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000209:etiology / Q000276:immunology / Q000517:prevention & control
D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D016572:Cyclosporine