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Examining the relationship between impaired host resistance and altered immune function in mice treated with TCDD
Beth A Vorderstrasse1, Andrea A Bohn, B Paige Lawrence
1Department of Pharmaceutical Sciences, Washington State University, Wegner Hall, Pullman, WA 99264-6534, USA.
Abstract:
Exposure to TCDD suppresses the immune response to numerous antigens, including bacterial and viral pathogens. Although we administer a non-lethal infection with influenza A virus, we often observe significant mortality in TCDD-treated animals. With the goal of identifying which TCDD-induced defects impair host resistance, we conducted a dose response study to examine whether alteration of particular immunological endpoints could be correlated with mortality. C57Bl/6 mice were treated with vehicle control, or 1, 2.5, 5, 7.5 or 10 microg/kg TCDD 1 day prior to intranasal (i.n.) infection with influenza virus. Survival was monitored for 9 days, when remaining mice were sacrificed and multiple endpoints evaluated. Lymphocyte migration to the lung and the production of virus-specific IgG2a, IgG1, and IgG2b antibodies were significantly diminished, even at the lower doses. IgA was enhanced in all groups treated with TCDD. In contrast, T cell expansion in the lymph node, and the production of IFNgamma and IL-12 were relatively resistant to suppression. Treatment with TCDD also enhanced pulmonary neutrophilia in infected mice. These results suggest that decreased antibody production and hyperinflammation may contribute to the death of TCDD-treated mice, and underscore the importance of evaluating numerous endpoints before concluding that a chemical is or is not immunotoxic.
Insights
Toxaphene dioxin (TCDD) exposure significantly increases mortality in mice infected with influenza A virus. This occurs due to suppressed antibody production and enhanced lung inflammation, highlighting TCDD
Area of Science:
- Immunotoxicology
- Environmental Health
- Virology
Background:
- Exposure to TCDD, a potent environmental contaminant, is known to suppress immune responses.
- TCDD-treated animals often exhibit increased mortality following viral infections, even with non-lethal pathogen doses.
Purpose of the Study:
- To investigate the dose-dependent effects of TCDD on host resistance during influenza A virus infection.
- To identify specific immunological defects induced by TCDD that correlate with increased mortality.
Main Methods:
- C57Bl/6 mice were treated with varying doses of TCDD (1-10 microg/kg) or vehicle control one day before intranasal influenza A virus infection.
- Survival was monitored for 9 days, followed by sacrifice and evaluation of multiple immunological endpoints in the lungs and lymph nodes.
Main Results:
- TCDD significantly suppressed lymphocyte migration to the lung and the production of virus-specific IgG antibodies (IgG2a, IgG1, IgG2b) in a dose-dependent manner.
- While T cell expansion and key cytokine production (IFN-gamma, IL-12) were relatively resistant to TCDD, IgA production was enhanced.
- TCDD treatment led to increased pulmonary neutrophilia in infected mice.
Conclusions:
- Decreased antibody production and TCDD-induced hyperinflammation in the lungs appear to be critical factors contributing to mortality.
- A comprehensive evaluation of multiple immunological parameters is essential for accurate assessment of chemical immunotoxicity.