CD40/CD154 blockade inhibits dendritic cell expression of inflammatory cytokines but not costimulatory molecules

Ivana R. Ferrer, Danya Liu, David F. Pinelli, Brent H. Koehn, Linda L. Stempora, Mandy L. Ford*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Blockade of the CD40/CD154 pathway remains one of the most effective means of promoting graft survival following transplantation. However, the effects of CD40/CD154 antagonism on dendritic cell (DC) phenotype and functionality following transplantation remain incompletely understood. To dissect the effects of CD154/CD40 blockade on DC activation in vivo, we generated hematopoietic chimeras in mice that expressed a surrogate minor Ag (OVA). Adoptive transfer of OVA-specific CD4+ and CD8+ T cells led to chimerism rejection, which was inhibited by treatment with CD154 blockade. Surprisingly, CD154 antagonism did not alter the expression of MHC and costimulatory molecules on CD11c+ DCs compared with untreated controls. However, DCs isolated from anti-CD154-treated animals exhibited a significant reduction in inflammatory cytokine secretion. Combined blockade of inflammatory cytokines IL-6 and IL-12p40 attenuated the expansion of Ag-specific CD4+ and CD8+ T cells and transiently inhibited the rejection of OVA-expressing cells. These results suggest that a major effect of CD154 antagonism in vivo is an impairment in the provision of signal three during donor-reactive T cell programming, as opposed to an impact on the provision of signal two. We conclude that therapies designed to target inflammatory cytokines during donor-reactive T cell activation may be beneficial in attenuating these responses and prolonging graft survival.

Original languageEnglish (US)
Pages (from-to)4387-4395
Number of pages9
JournalJournal of Immunology
Volume189
Issue number9
DOIs
StatePublished - Nov 1 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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