Combination treatment with donor-specific transfusions and cyclosporine a induces long-term survival of cardiac allografts in miniature Swine.
BACKGROUND
To evaluate whether pretransplant donor-specific transfusions (DST) can induce tolerance to cardiac allografts in large animals, heterotopic cardiac transplants were performed across a class I MHC barrier in inbred miniature swine.


METHODS
Experimental animals received two DSTs, each containing 1.4x10 viable peripheral blood mononuclear cells, 14 and 7 days prior to transplantation together with a 12-day course of cyclosporine (CyA) (13 mg/kg IV) starting on postoperative day (POD) 0.


RESULTS
Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA alone (n=3) exhibited graft survival to 53, 52 and 59 days. In contrast, the combination of DST and CyA (n=3) led to stable graft function for >200 days. Long-term survivors maintained peripheral CML response against donor antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased (P=0.011), and a significant number of CD8+ T cells underwent apoptosis (10.1% on POD 0; 5.2% on POD -14; P=0.04). None of the DST-treated animals developed donor-specific antibodies.


CONCLUSIONS
These results are the first to demonstrate the ability of DST to induce operational tolerance to cardiac allografts in large animals, and they suggest that peripheral mechanisms of tolerance mediate this effect.
Hoerbelt
Ruediger
R
Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Johnston
Douglas R
DR
Shoji
Tsuyoshi
T
Houser
Stuart L
SL
Hasse
Rebecca S
RS
Ledgerwood
Levi G
LG
Iribarne
Alexander
A
Allan
James S
JS
Sayegh
Mohamed H
MH
Sachs
David H
DH
Madsen
Joren C
JC
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001803:Blood Transfusion; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology; D013997:Time Factors; D014019:Tissue Donors; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine