Baboons undergoing orthotopic concordant cardiac xenotransplantation surviving more than 300 days: effect of immunosuppressive regimen.
OBJECTIVE
We reviewed long-term survival among hosts in 3 consecutive series of a rhesus monkey-baboon orthotopic cardiac xenotransplantation model with reference to host immune response, including the effectiveness in preventing rejection and limiting toxicity concerning infection, to evaluate specific immunosuppressive regimens for long-term outcomes.


METHODS
Six juvenile baboons surviving more than 300 days after transplantation were reviewed. Regimen A consisted of splenectomy, FK506, methotrexate, and antilymphocyte globulin. Regimen B consisted of pretransplantation and chronic maintenance with cyclosporine A (INN: ciclosporin), methotrexate, and antithymocyte globulin. Regimen C was the same as regimen B plus pretransplantation total lymphoid irradiation and intraoperative donor bone marrow cell infusion. Rejections were detected by means of echocardiography.


RESULTS
Long-term survivors in 3 groups were followed for a range of 332 to 515 days (mean, 436 days). Rejection frequency in regimens A, B, and C was 0.35, 0.58, and 0.18 per month, and rescue therapy days were 23 (4.8%), 123 (9.5%), and 20 (2.4%), respectively (P <.0001). Infection frequency was 0.58, 0.56, and 0.19 per month, and therapy days were 192 (38.2%), 164 (12.6%), and 7 (0.9%), respectively (P <.0001). Concerning the host immune response, interleukin 2-activated T cells of all groups during rejection-free periods showed lower numbers compared with those of control animals (P <.0005), and regimen C was the lowest among 3 groups (P <.01). The production of xenoantibody was sufficiently attenuated in all groups.


CONCLUSIONS
Regimen C leads to long-term survival with fewer rejection and infection episodes by means of suppression of the interleukin 2 pathway and xenoantibody production.
Asano
Miki
M
Department of Surgery and Immunology Center, Loma Linda University Medical School and Medical Center, Loma Linda, Calif. 92354, USA. Steven.Gundry@tenethealth.com
Gundry
Steven R
SR
Izutani
Hironori
H
Cannarella
Sandra Nehlsen
SN
Fagoaga
Omar
O
Bailey
Leonard L
LL
D000206:Actuarial Analysis; D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000453:epidemiology; D016027:Heart Transplantation / Q000276:immunology / Q000401:mortality; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007239:Infections / Q000453:epidemiology; D008253:Macaca mulatta; D008727:Methotrexate / Q000627:therapeutic use; D010215:Papio; D013156:Splenectomy; D016559:Tacrolimus / Q000627:therapeutic use; D013997:Time Factors; D014183:Transplantation, Heterologous
D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus; D008727:Methotrexate