Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates

• Type of Material: Article
• Authors: AM Freitas, Emory University; KP Samy, Duke University; Alton Farris III, Emory University; FV Leopardi, Duke University; M Song, Duke University; L Stempora, Duke University; Elizabeth Strobert, Emory University; JA Jenkins, Yerkes National Primate Research Center; Allan Kirk, Emory University; LC Cendales, Duke University
• Language: English
• Date: 2015-07-02
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.13379
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 15
• Issue: 8
• Start Page: 2240
• End Page: 2249
• Grant/Funding Information: This study was supported by a grant from the Department of Defense administered through the Navy Bureau of Medicine and Surgery’s Medical Development Program, by the American Society of Transplant Surgeons, by the Melina Nakos Foundation, and by resources at the Atlanta VA Medical Center.
• Keywords: Transplantation; RAPAMYCIN; Life Sciences & Biomedicine; TISSUE ALLOTRANSPLANTATION; SURVIVAL; T-CELLS; TRANSPLANTATION; SIROLIMUS-BASED IMMUNOSUPPRESSION; Science & Technology; Surgery; BELATACEPT; WOUND-HEALING COMPLICATIONS; ALEFACEPT
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the nonlifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a nonhuman-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2hi memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model.