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Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques.

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138.5 Kb
Date
2012-09
Authors
Page, EK
Page, AJ
Kwun, J
Gibby, AC
Leopardi, F
Jenkins, JB
Strobert, EA
Song, M
Hennigar, RA
Iwakoshi, N
Knechtle, SJ
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(11 total)
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Abstract
Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.
Type
Journal article
Subject
Animals
Graft Rejection
Graft Survival
Immunohistochemistry
Immunologic Memory
Immunosuppressive Agents
Isoantibodies
Lymphocyte Depletion
Macaca mulatta
Male
Permalink
https://hdl.handle.net/10161/10061
Published Version (Please cite this version)
10.1111/j.1600-6143.2012.04074.x
Publication Info
Page, EK; Page, AJ; Kwun, J; Gibby, AC; Leopardi, F; Jenkins, JB; ... Knechtle, SJ (2012). Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques. Am J Transplant, 12(9). pp. 2395-2405. 10.1111/j.1600-6143.2012.04074.x. Retrieved from https://hdl.handle.net/10161/10061.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Knechtle

Stuart Johnston Knechtle

William R. Kenan, Jr. Distinguished Professor
During my career as an academic surgeon, I have had the privilege of leading and/or participating in a diverse portfolio of hypothesis-driven research projects.  These projects have centered on the immunology of surgery and transplantation, including both cellular and antibody-mediated immune responses.  During my training I studied the response of hyper-sensitized recipients to allogeneic liver transplantation, and am currently studying means of reducing immunologic memory that might
Kwun

Jean Kwun

Assistant Professor in Surgery
Research interests include humoral tolerance to organ transplants in animal model and humans, developing a clinically relevant animal model to study the mechanisms of antibody-mediated rejection (AMR), and establishing a conceptual basis that will translate into therapeutic intervention of AMR.
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