Portal Venous Donor‐Specific Transfusion in Conjunction with Sirolimus Prolongs Renal Allograft Survival in Nonhuman Primates

• Published in: American journal of transplantation Vol. 9; no. 1; pp. 124 - 131
• Main Authors: Dhanireddy, K. K., Bruno, D. A., Weaver, T. A., Xu, H., Zhang, X., Leopardi, F. V., Hale, D. A., Kirk, A. D.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.01.2009; Wiley
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Chimera; Donor‐specific transfusion; Graft Rejection - prevention & control; Graft Survival; Immune Tolerance; Immunosuppressive Agents - therapeutic use; Isoantigens - administration & dosage; Kidney Transplantation; Macaca mulatta; Medical sciences; Pharmacology. Drug treatments; Primates; rhesus monkey; Sirolimus - therapeutic use; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; tolerance; Antineoplastic agent; Suboptimal donor; Prognosis; Transfusion; Intravenous administration; Sirolimus; Monkey; Transplantation; Macaca mulatta; Homotransplantation; Kidney; Macrocycle; Surgery; Primates; Simioidea; Graft; Protein synthesis inhibitor; Human; Donor-specific transfusion; Nonhuman primate; Tolerance; Lactone; Macrolide; Survival; rhesus monkey; Vertebrata; Antibiotic; Mammalia; Treatment; Urinary system; Immunosuppressive agent; Portal vein; Antibacterial agent; Prolonged
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2008.02448.x

Pretransplant exposure to donor antigen is known to modulate recipient alloimmunity, and frequently results in sensitization. However, donor‐specific transfusion (DST) can have a protolerant effect that is dependent on route, dose and coadministered immunosuppression. Rodent studies have shown in some strain combinations that portal venous (PV) DST alone can induce tolerance, and uncontrolled clinical use of PVDST has been reported. In order to determine if pretransplant PVDST has a clinically relevant salutary effect, we studied it and the influence of concomitant immunosuppression in rhesus monkeys undergoing renal allotransplantation. Animals received PVDST with unfractionated bone marrow and/or tacrolimus or sirolimus 1 week prior to transplantation. Graft survival was assessed without any posttransplant immunosuppression. PVDST alone or in combination with tacrolimus was ineffective. However, PVDST in combination with sirolimus significantly prolonged renal allograft survival to a mean of 24 days. Preoperative sirolimus alone had no effect, and peripheral DST with sirolimus prolonged graft survival in 2/4 animals, but resulted in accelerated rejection in 2/4 animals. These data demonstrate that PVDST in combination with sirolimus delays rejection in a modest but measurable way in a rigorous model. It may thus be a preferable method for donor antigen administration. A preoperative donor specific blood transfusion administered via the portal vein significantly delays the onset of acute renal allograft rejection in rhesus monkeys when delivered in combination with sirolimus but not tacrolimus.