The Aryl hydrocarbon receptor (AhR) mediates the toxic effects of a broad class of environmental contaminants, the halogenated aromatic hydrocarbons. Moreover, the immune system is a very sensitive target of the prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-induced immune dysfunction is characterized by profound suppression of T cell-mediated immunity and increased susceptibility to disease. Dendritic cells (DC) that function to induce the activation, expansion and differentiation of T cells are postulated to be direct targets of TCDD. DC aberrantly express critical costimulatory molecules and undergo premature deletion from immune tissues following AhR activation by TCDD. Therefore, we hypothesize AhR activation in DC causes defects in their activation and/or survival and ultimately contributes to the suppression of adaptive immunity. The focus of this laboratory is to understand the cellular and molecular basis for the potent immune suppression induced by AhR ligands, while the primary objective of this proposal is to determine the mechanisms underlying TCDD-induced suppression of DC functions. These objectives will be determined by the following four Specific Aims: (1) to define the role of AhR activation in the fate and function of DC; (2) to determine if the effects of AhR activation in DC are mediated exclusively via the Dioxin Response Element (ORE); and (3) to investigate the involvement of the Fas/Fas ligand pathway and cell cycle perturbation in AhR-mediated DC death. The research proposed in this application will have significant, positive effects on human health. This work will advance our basic understanding of DC interactions with antigen-specific T cells. It will define mechanisms of xenobiotic-induced immunotoxicity, and may identify novel therapeutic approaches to generate tolerogenic DC. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES013784-01A1
Application #
7039381
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Tinkle, Sally S
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$333,155
Indirect Cost
Name
University of Montana
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
010379790
City
Missoula
State
MT
Country
United States
Zip Code
59812
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Kreitinger, Joanna M; Beamer, Celine A; Shepherd, David M (2016) Environmental Immunology: Lessons Learned from Exposure to a Select Panel of Immunotoxicants. J Immunol 196:3217-25
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