title: Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates.
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 CD2(hi) 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.
authors.affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: A M
authors.initials: AM
authors.lastname: Freitas
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC.
authors.forename: K P
authors.initials: KP
authors.lastname: Samy
authors.affiliation: Department of Pathology & Laboratory Medicine, Emory University, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC.
authors.forename: F V
authors.initials: FV
authors.lastname: Leopardi
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC.
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC.
authors.forename: L
authors.initials: L
authors.lastname: Stempora
authors.affiliation: Yerkes National Primate Research Center, Atlanta, GA.
authors.forename: E A
authors.initials: EA
authors.lastname: Strobert
authors.affiliation: Yerkes National Primate Research Center, Atlanta, GA.
authors.forename: J A
authors.initials: JA
authors.lastname: Jenkins
authors.affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.|Department of Surgery, Duke University Medical Center, Durham, NC.
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC.
authors.forename: L C
authors.initials: LC
authors.lastname: Cendales
mesh_terms: D064591:Allografts; D000818:Animals; D009389:Neovascularization, Pathologic; D011323:Primates
keywords: animal models: nonhuman primate; calcineurin inhibitor (CNI); costimulation; fusion proteins and monoclonal antibodies: belatacept; immunosuppressant; reconstructive transplantation; rejection; translational research/science; vascularized composite