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 (T CDD) suppressed the induction of the costimulatory molecule CD86 (B7-2) on B220+ and Mac-1+ spleen cells following the injection of allogeneic P815 tu mor cells. In this study, TCDD exposure was shown to suppress CD54 and majo r histocompatibility complex (MHC) class II expression on B220+, Mac-1+, an d CD11c+ splenic antigen presenting cells (APC). Furthermore, interleukin-1 2 (IL-12) production by spleen cells from P815-immunized mice was significa ntly decreased following exposure to TCDD. To determine if exogenous costim ulation 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 splen ic APC and greatly enhanced the production of interleukin-12. TCDD treatmen t had minimal effects on the anti-CD40-induced expression of accessory mole cules on splenic APC. TCDD exposure had no effect on anti-CD40-induced IL-1 2 in the plasma but suppressed its production from cultured spleen cells. S urprisingly, although stimulation via CD40 increased the activation of APC, allograft effector functions were not restored in TCDD-treated mice, perha ps due to persistent defects in antigen processing and presentation, cytoki ne production, T cell function, or CD40-independent pathways of APC activat ion. (C) 2001 Academic Press.