Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques.
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 articleSubject
AnimalsGraft Rejection
Graft Survival
Immunohistochemistry
Immunologic Memory
Immunosuppressive Agents
Isoantibodies
Lymphocyte Depletion
Macaca mulatta
Male
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https://hdl.handle.net/10161/10061Published Version (Please cite this version)
10.1111/j.1600-6143.2012.04074.xPublication 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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Show full item recordScholars@Duke
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
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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