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

• Type of Material: Article
• Authors: K. K. Dhanireddy, Georgetown University Hospital; D. A. Bruno, Georgetown University Hospital; T. A. Weaver, Emory University; H. Xu, Department of Health and Human Services; X. Zhang, Department of Health and Human Services; F. V. Leopardi, Emory University; D. A. Hale, Department of Health and Human Services; Allan D Kirk, Emory University
• Language: English
• Date: 2009-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 The American Society of Transplantation and the American Society of Transplant Surgeons
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2008.02448.x/abstract;jsessionid=DC491D7AA4E72DDF727E8852971F518D.f04t01
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 9
• Issue: 1
• Start Page: 124
• End Page: 131
• Grant/Funding Information: TAW was supported by the Howard Hughes Medical Institute.; National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK; ADK is supported by the Georgia Research Alliance and by the McKelvey Foundation.; Salary support for KKD was provided by the Department of Surgery, Georgetown University Hospital. Salary support for DAB was provided by the ASTS-NKF Folkert Belzer Research Award.; This study was funded in part by the Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health.
• Keywords: tolerance; rhesus monkey; Donor-specific transfusion
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, General

Abstract

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.