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

E. K. Page, A. J. Page, J. Kwun, A. C. Gibby, F. Leopardi, J. B. Jenkins, E. A. Strobert, M. Song, R. A. Hennigar, N. Iwakoshi, S. J. Knechtle

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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. Homeostatic repopulation of CD4 + memory T cells enhances early alloantibody production and antibody-mediated renal allograft injury in CD3-specific immunotoxin-treated rhesus macaques.

Original languageEnglish (US)
Pages (from-to)2395-2405
Number of pages11
JournalAmerican Journal of Transplantation
Volume12
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Keywords

  • Anti-CD3 immunotoxin
  • T cell depletion
  • antibody-media-ted rejection
  • de novo alloantibodies
  • kidney transplantation
  • nonhuman primate model

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