TY - JOUR
T1 - Anti-CD40 treatment of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed C57BI/6 mice induces activation of antigen presenting cells yet fails to overcome TCDD-induced suppression of allograft immunity
AU - Shepherd, David M.
AU - Steppan, Linda B.
AU - Hedstrom, Olaf R.
AU - Kerkvliet, Nancy I.
N1 - Funding Information:
The authors thank Julie Oughton and Kay Fischer for expert technical support. We thank the Environmental Health Science Center for use of the flow cytometry facility. Also, the authors thank Dr. Rodney A. Prell, Dr. B. Paige Lawrence, and Dr. Randy J. Noelle for helpful discussions. This research was supported by grants from the National Institutes of Environmental Health Sciences (EHSC Grant ES00210, Program Project P01-ES00040, and R01-ES03966).
PY - 2001/1/1
Y1 - 2001/1/1
N2 - We have previously demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed the induction of the co-stimulatory molecule CD86 (B7-2) on B220+ and Mac-l+ 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-l+, 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.
AB - We have previously demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed the induction of the co-stimulatory molecule CD86 (B7-2) on B220+ and Mac-l+ 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-l+, 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.
KW - Antigen presenting cells
KW - Cell-mediated immunity
KW - Immunotoxicity
KW - TCDD
UR - http://www.scopus.com/inward/record.url?scp=0035148487&partnerID=8YFLogxK
U2 - 10.1006/taap.2000.9080
DO - 10.1006/taap.2000.9080
M3 - Article
C2 - 11141351
AN - SCOPUS:0035148487
SN - 0041-008X
VL - 170
SP - 10
EP - 22
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 1
ER -