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

David M. Shepherd, Linda B. Steppan, Olaf R. Hedstrom, Nancy I. Kerkvliet

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)10-22
Number of pages13
JournalToxicology and Applied Pharmacology
Volume170
Issue number1
DOIs
StatePublished - Jan 1 2001

Keywords

  • Antigen presenting cells
  • Cell-mediated immunity
  • Immunotoxicity
  • TCDD

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