Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques.
Published
Journal Article
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.
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Duke Authors
Cited Authors
- Page, EK; Page, AJ; Kwun, J; Gibby, AC; Leopardi, F; Jenkins, JB; Strobert, EA; Song, M; Hennigar, RA; Iwakoshi, N; Knechtle, SJ
Published Date
- September 2012
Published In
Volume / Issue
- 12 / 9
Start / End Page
- 2395 - 2405
PubMed ID
- 22776408
Pubmed Central ID
- 22776408
Electronic International Standard Serial Number (EISSN)
- 1600-6143
Digital Object Identifier (DOI)
- 10.1111/j.1600-6143.2012.04074.x
Language
- eng
Conference Location
- United States