Polychlorinated dibenzo-p-dioxin (PCDD) and structurally related halogenated aromatic hydrocarbons, including the dibenzofurans and biphenyls, are widely distributed, highly toxic environmental contaminants that produce a similar and characteristic pattern of toxic and biochemical responses in animals. Structure/activity studies suggest that the toxic isomers of these chemicals act through a common receptor (the Ah receptor) which regulates the expression of a multitude of gene batteries. In all species studied, the toxic congeners produce thymic involution and suppression of the immune response, which also is mediated, at least in part, by the Ah receptor. However despite considerable investigation, the precise nature of the immune dysfunction and the target cells affected by these chemicals have not been determined. The cell membrane antigens and receptors displayed by lymphocyte/monocyte subsets phenotypically define the cells, and, with several markers, are associated with specific functions. Therefore, modulation of the expression of these cell-surface molecules by exposure to dioxin could be expected to have significant effects on cell behavior. Since the Ah receptor regulates the expression of multiple, and, as yet, not fully defined gene batteries, it is possible that activation of the Ah gene produces altered surface antigen or receptor expression which, in turn, alters the functional activity of the cell.
The specific aims of this proposal are: 1) to characterize lymphocyte/monocyte subpopulations in control and dioxin-treated mice in terms of cell-surface marker expression using multiparameter flow cytometry, 2) to characterize relative changes in lymphocyte/monocyte subpopulations following antigen challenge in control and dioxin-exposed mice by multiparameter flow cytometry, and 3) to determine if in vitro exposure of lymphocyte/monocyte subsets to dioxin produces similar alterations in surface antigen expression observed after in vivo exposure that may then be utilized for the study of dioxin-induced effects on the human immune system. Quantitative and qualitative surface marker expression of Ia, IgM, IgD, C3, Thy-1, Lyt-1, Lyt-2, L3T4 and I-J will be analyzed in response to exposure to 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, a major immunosuppressive contaminant of technical grade pentachlorophenol. Other dioxin isomers will be examined if positive results are found with HpCCD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003966-03
Application #
3251737
Study Section
Toxicology Study Section (TOX)
Project Start
1986-05-01
Project End
1990-04-30
Budget Start
1988-05-01
Budget End
1990-04-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Oregon State University
Department
Type
Schools of Veterinary Medicine
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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