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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003966-10
Application #
2684397
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1986-05-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
2000-03-31
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Oregon State University
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Marshall, Nikki B; Kerkvliet, Nancy I (2010) Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells. Ann N Y Acad Sci 1183:25-37
Vorderstrasse, Beth A; Dearstyne, Erica A; Kerkvliet, Nancy I (2003) Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antigen-presenting activity of dendritic cells. Toxicol Sci 72:103-12
Shepherd, D M; Steppan, L B; Hedstrom, O R et al. (2001) 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. Toxicol Appl Pharmacol 170:10-22
Vorderstrasse, B A; Kerkvliet, N I (2001) 2,3,7,8-Tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules. Toxicol Appl Pharmacol 171:117-25
Shepherd, D M; Dearstyne, E A; Kerkvliet, N I (2000) The effects of TCDD on the activation of ovalbumin (OVA)-specific DO11.10 transgenic CD4(+) T cells in adoptively transferred mice. Toxicol Sci 56:340-50
Prell, R A; Dearstyne, E; Steppan, L G et al. (2000) CTL hyporesponsiveness induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin: role of cytokines and apoptosis. Toxicol Appl Pharmacol 166:214-21
Shepherd, D M; Kerkvliet, N I (1999) Disruption of CD154:CD40 blocks generation of allograft immunity without affecting APC activation. J Immunol 163:2470-7
Kerkvliet, N I; Baecher-Steppan, L; Shepherd, D M et al. (1996) Inhibition of TC-1 cytokine production, effector cytotoxic T lymphocyte development and alloantibody production by 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Immunol 157:2310-9
Moos, A B; Kerkvliet, N I (1995) Inhibition of tumor necrosis factor activity fails to restore 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced suppression of the antibody response to sheep red blood cells. Toxicol Lett 81:175-81
DeKrey, G K; Kerkvliet, N I (1995) Effects of exogenous corticosterone treatment on alloantigen-specific cytotoxic T lymphocyte activity in mice. J Pharmacol Exp Ther 273:823-9

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