Inhibition of NF-kappa B during human dendritic cell differentiation generates anergy and regulatory T-cell activity for one but not two human leukocyte antigen DR mismatches.
We examined the in vitro inhibition of human monocyte-derived dendritic cells (DC) maturation via NF-kappaB blockade on T-cell allostimulation, cytokine production, and regulatory T-cell generation. DC were generated from CD14+ monocytes isolated from peripheral blood using GM-CSF and IL-4 for differentiation and TNF-alpha, IL-1beta, and PGE2 as maturational stimuli with or without the NF-kappaB inhibitors, BAY 11-7082 (BAY-DC) or Aspirin (ASA-DC). Stimulator and responder cells were one versus two HLA-DR mismatched in direct versus indirect presentation assays. Both BAY-DC and ASA-DC expressed high levels of HLA-DR and CD86 but always expressed less CD40 compared with controls. Some experiments showed slightly lower levels of CD80. Both BAY- and ASA-allogeneic DC and autologous alloantigen pulsed DC were weaker stimulators of T cells (by MLR) compared with controls, and there was reduced IL-2 and IFN-gamma production by T cells stimulated with BAY-DC or ASA-DC (by ELISPOT) (more marked results were always observed with ASA-treated DC). In addition, NF-kappaB blockade of DC maturation caused the generation of T cells with regulatory function (T regs) but only when T cells were stimulated by either allogeneic (direct presentation) or alloantigen pulsed autologous DC (indirect presentation) with one HLA-DR mismatch and not with two HLA-DR mismatches (either direct or indirect presentation). However, the T regs generated from these ASA-DC showed similar FoxP3 mRNA expression to those from nontreated DC. Extension of this study to human organ transplantation suggests potential therapies using one DR-matched NF-kappaB blocked DC to help generate clinical tolerance.
Hernandez
Ana
A
Department of Surgery, Division of Transplantation, University of Miami School of Medicine, Miami, FL, USA.
Burger
Melissa
M
Blomberg
Bonnie B
BB
Ross
William A
WA
Gaynor
Jeffrey J
JJ
Lindner
Inna
I
Cirocco
Robert
R
Mathew
James M
JM
Carreno
Manuel
M
Jin
Yidi
Y
Lee
Kelvin P
KP
Esquenazi
Violet
V
Miller
Joshua
J
D001241:Aspirin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects; D006684:HLA-DR Antigens / Q000032:analysis* / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D006684:HLA-DR Antigens; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D001241:Aspirin