Role of the thymus in transplantation tolerance in miniature swine: V. Deficiency of the graft-to-thymus pathway of tolerance induction in recipients of cardiac transplants.
BACKGROUND
We have previously shown that both thymic immigrants (graft to thymus pathway) and thymic emigrants (thymus to graft pathway) are involved in tolerance to renal allografts in miniature swine treated with a short course of calcineurin inhibitors. This study investigates the role of these pathways in cardiac transplant survival in recipients treated with a short course of tacrolimus.


METHODS
Eleven animals received two-haplotype fully MHC-mismatched cardiac grafts with a 12-day course of tacrolimus. Recipients were thymectomized on day -21 (n=5) or day 0 (n=3), or were left euthymic (n=3). Two of the day -21 thymectomized animals received a day 0 host-MHC matched thymocyte infusion.


RESULTS
Euthymic recipients of cardiac grafts treated with an immunosuppressive regimen identical to that previously shown to induce tolerance in euthymic recipients of renal allografts all rejected their grafts. Although no animal became tolerant, animals that were euthymic or thymectomized on day 0, as well as recipients of day 0 host-type thymocyte infusions following thymectomy on day -21, developed donor-specific hyporesponsiveness and maintained their cardiac grafts for markedly prolonged periods. In contrast, all animals thymectomized on day -21 that did not receive thymocyte infusions developed strong antidonor CTL responses and rejected their grafts by day 35.


CONCLUSIONS
The graft-to-thymus pathway that plays an important role in tolerance induction to renal allografts appears to be relatively deficient in recipients of cardiac grafts. Strategies to increase donor antigen migration to the host thymus might therefore assist in tolerance induction to cardiac allografts.
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
Shin
S
Yamamoto
Katsuhito
K
Teranishi
Chisako
C
Kamano
Emma
E
Samelson-Jones
Hitoshi
H
Arakawa
Shuji
S
Nobori
Masayoshi
M
Okumi
Stuart
S
Houser
Akira
A
Shimizu
David H
DH
Sachs
Kazuhiko
K
Yamada
D000818:Animals; D016027:Heart Transplantation / Q000276:immunology*; D006650:Histocompatibility Testing; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D023421:Models, Animal; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000276:immunology*; D013934:Thymectomy; D013950:Thymus Gland / Q000276:immunology*; D014181:Transplantation Immunology; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous / Q000276:immunology
D007166:Immunosuppressive Agents