The Immune system has been identified as one of the most sensitive targets for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related halogenated aromatic hydrocarbons (HAH). The Environmental Protection Agency recently completed a reassessment of the health risks associated with environmental contamination by these chemicals. Based on a draft of the risk characterization document, TCDD affects the immune and reproductive systems at exposure levels lower than the carcinogenic dose. Thus, for the first time, data from animal studies on the immunotoxicity and reproductive toxicity of TCDD may be used as the basis for setting acceptable levels in the environment. It is therefore of great importance that we improve our understanding of the mechanisms that underlie these toxicities in order to improve our ability to extrapolate from animals to humans and to most accurately predict human health effects. Previous studies in our laboratory have shown that' exposure of C57B1/6 mice to HAH induces an Ah-receptor dependent, dose- dependent suppression of cytotoxic T lymphocyte (CTL) activity following the injection of allogeneic P815 tumor cells. Our overall goals are to understand the cellular and molecular basis by which HAH suppress allograft immunity as a model for understanding the overall impact of these widespread environmental toxicants on immune function. In studies carried out during the current grant period we have shown that suppression of CTL activity by HAH is correlated with a profound decrease in splenic production of interferon-gamma (IFN-gamma). Interleukin (IL)- 2 production is also modulated by HAH exposure, but the effects are characterized by an early elevation followed by a later suppression of IL-2 levels. In contrast, the production of IL-6 and IL-4 was not suppressed by HAH exposure even though the alloantibody response is suppressed by HAH exposure in parallel with the suppression of the CTL response. The studies proposed in this grant application are based on- the hypothesis that the alterations in cytokine production underlie the suppression of allograft immunity in HAH-treated mice. Using 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) as the prototype AhR ligand, five specific aims will be addressed: l) to define the roles of suppressed IFN-g and altered IL-2 production in the suppression of CTL activity and the alloantibody response to P8l5 tumor cells in TCDD-treated mice; 2) to characterize the cells responsible for the production of IFN-gamma and IL-2 in the allograft response; 3) to characterize by phenotype and function a TCDD-induced population of Mac-l+ cells in the spleen; 4) to further characterize the effects of TCDD exposure on the early cytokine response to allografted P815 tumor cells, focusing on IL-12, TGF-beta, IL-1 and TNF as important regulators of T cell activation; and 3) based on preliminary data that demonstrate a reduced expression of B7-1 and B7- 2 on splenic Mac-1+ and B220+ cells from TCDD treated mice, to investigate the role of altered expression of these and other costimulatory molecules on antigen presenting cells (APC) as the defective link in T cell activation in this model.
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