Efficacy and toxicity of a protocol using sirolimus, tacrolimus and daclizumab in a nonhuman primate renal allotransplant model.
A regimen combining sirolimus, tacrolimus, and daclizumab has recently been shown to provide adequate immunosuppression for allogeneic islet transplantation in humans, but remains unproven for primarily vascularized allografts. We evaluated this regimen for renal allograft transplantation in mismatched nonhuman primates. Dosages of sirolimus and tacrolimus were adjusted for trough levels of 10-15 ng/mL and 4-6 ng/mL, respectively. Treated monkeys (n = 5) had significantly prolonged allograft survival, with a mean survival of 36 days vs. 7 days in untreated controls (n = 6, p = 0.008). Four of five treated animals, but none of the controls, developed fibrinoid vascular necrosis of the small intestine. A review of gut histology from animals on other immunosuppressive protocols performed by our laboratory suggested that these lesions were a result of sirolimus exposure. In summary, this regimen prolongs the survival of vascularized renal allografts, but is limited by profound GI toxicity in rhesus macaques.
NIDDK/Navy Transplantation and Autoimmunity Branch, Naval Medical Research Center, Bethesda, Maryland 20892, USA.
Sean P
SP
Montgomery
Steven R
SR
Mog
He
H
Xu
Douglas K
DK
Tadaki
Boaz
B
Hirshberg
Justin D
JD
Berning
John
J
Leconte
David M
DM
Harlan
Douglas
D
Hale
Allan D
AD
Kirk
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000077561:Daclizumab; D005069:Evaluation Studies as Topic; D006085:Graft Survival / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000633:toxicity; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation; D008253:Macaca mulatta / Q000276:immunology; D023421:Models, Animal; D020123:Sirolimus / Q000494:pharmacology* / Q000633:toxicity*; D016559:Tacrolimus / Q000494:pharmacology* / Q000633:toxicity*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000077561:Daclizumab; D020123:Sirolimus; D016559:Tacrolimus