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Author Notes:

Corresponding Author: Mandy L. Ford, Ph.D., Assistant Professor, Emory Transplant Center, Dept. of Surgery, Emory University, 101 Woodruff Rd., Suite 5105, Atlanta, GA 30322; Office: 404-727-2900; Lab: 404-727-5854; Fax: 404-727-3660; Email: mandy.ford@emory.edu

Ivana R. Ferrer and Danya Liu contributed equally.

The authors have no financial conflicts of interest.


Research Funding:

This work was supported by NIH/NIAID AI073707 and AI079409 to MLF.

CD40/CD154 Blockade Inhibits Dendritic Cell Expression of Inflammatory Cytokines but Not Costimulatory Molecules


Journal Title:

Journal of Immunology


Volume 189, Number 9


, Pages 4387-4395

Type of Work:

Article | Post-print: After Peer Review


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 antagonsim 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 antigen (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+ DC compared to 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 antigen-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.

Copyright information:

© 2012 by The American Association of Immunologists, Inc.

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