title: CD40/CD154 blockade inhibits dendritic cell expression of inflammatory cytokines but not costimulatory molecules.
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.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ivana R
authors.initials: IR
authors.lastname: Ferrer
authors.forename: Danya
authors.initials: D
authors.lastname: Liu
authors.forename: David F
authors.initials: DF
authors.lastname: Pinelli
authors.forename: Brent H
authors.initials: BH
authors.lastname: Koehn
authors.forename: Linda L
authors.initials: LL
authors.lastname: Stempora
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000502:physiology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology; D002645:Chickens; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera; D015398:Signal Transduction / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D023201:CD40 Ligand