Alloimmunity in primate heart recipients with CD154 blockade: Evidence for alternative costimulation mechanisms

Agnes M. Azimzadeh, Steffen Pfeiffer, Guosheng Wu, Carsten Schröder, George L. Zorn, Shahrooz S. Kelishadi, Engin Ozkaynak, Marilyn Kehry, James B. Atkinson, Geraldine G. Miller, Richard N. Pierson

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Background. CD154 mediates key facets of humoral and cellular immunity to alloantigens, and is tolerogenic to influenza antigens in primates. Barriers to CD154-based tolerance induction for primate cardiac allografts have not previously been defined. Methods. Heterotopic cardiac allograft outcomes in cynomolgus monkeys treated with a CD154 inhibitor, IDEC-131 (n=27), were compared to no treatment (n=4) or cyclosporine A (n=6). Results. CD154 blockade significantly prolonged median allograft survival, from 6.2 (range 6, 7, n=4) days in untreated controls, to 39 (8, 112, n=16) days with intensive monotherapy and 93 (>25, 386; n=3) days with added antithymocyte globulin (ATG), but did not yield tolerance. Alloantibody production was delayed but not prevented by IDEC-131 alone or with ATG, and was exacerbated by infusion of donor bone marrow (n=8). Expression of ICOS was prominent in graft infiltrating lymphocytes, and preceded elaboration of antidonor antibody and vasculopathy. Conclusion. CD154 monotherapy modulates primate cardiac alloimmunity, but does not readily induce tolerance. Targeting alternative costimulation pathways, including ICOS, may facilitate tolerance induction based on CD154 blockade.

Original languageEnglish (US)
Pages (from-to)255-264
Number of pages10
JournalTransplantation
Volume81
Issue number2
DOIs
Publication statusPublished - Jan 1 2006

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Keywords

  • Alloantibody
  • Allotransplantation
  • CD40L (CD154)
  • Cardiac allograft vasculopathy
  • Chronic rejection
  • Costimulation
  • Heart transplant
  • ICOS
  • Primate
  • T-cell activation

ASJC Scopus subject areas

  • Transplantation

Cite this

Azimzadeh, A. M., Pfeiffer, S., Wu, G., Schröder, C., Zorn, G. L., Kelishadi, S. S., ... Pierson, R. N. (2006). Alloimmunity in primate heart recipients with CD154 blockade: Evidence for alternative costimulation mechanisms. Transplantation, 81(2), 255-264. https://doi.org/10.1097/01.tp.0000190099.62847.e6