Anti-CD40 Treatment of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed C57Bl/6 mice induces activation of antigen presenting cells yet fails to overcome TCDD-induced suppression of allograft immunity.
We have previously demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed the induction of the costimulatory molecule CD86 (B7-2) on B220+ and Mac-1+ spleen cells following the injection of allogeneic P815 tumor cells. In this study, TCDD exposure was shown to suppress CD54 and major histocompatibility complex (MHC) class II expression on B220+, Mac-1+, and CD11c+ splenic antigen presenting cells (APC). Furthermore, interleukin-12 (IL-12) production by spleen cells from P815-immunized mice was significantly decreased following exposure to TCDD. To determine if exogenous costimulation could enhance the activation of APC, vehicle- and TCDD-treated mice were injected with an agonistic antibody to murine CD40. Stimulation with anti-CD40 increased the expression of CD86, CD54, and MHC class II on splenic APC and greatly enhanced the production of interleukin-12. TCDD treatment had minimal effects on the anti-CD40-induced expression of accessory molecules on splenic APC. TCDD exposure had no effect on anti-CD40-induced IL-12 in the plasma but suppressed its production from cultured spleen cells. Surprisingly, although stimulation via CD40 increased the activation of APC, allograft effector functions were not restored in TCDD-treated mice, perhaps due to persistent defects in antigen processing and presentation, cytokine production, T cell function, or CD40-independent pathways of APC activation.
Shepherd
D M
DM
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, 97331, USA. David.Shepherd@orst.edu
Steppan
L B
LB
Hedstrom
O R
OR
Kerkvliet
N I
NI
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects*; D019013:CD40 Antigens / Q000187:drug effects*; D002452:Cell Count; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009929:Organ Size; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014181:Transplantation Immunology / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D004785:Environmental Pollutants; D007202:Indicators and Reagents; D000072317:Polychlorinated Dibenzodioxins