Examining the relationship between impaired host resistance and altered immune function in mice treated with TCDD.
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.
Department of Pharmaceutical Sciences, Washington State University, Wegner Hall, Pullman, WA 99264-6534, USA.
Beth A
BA
Vorderstrasse
Andrea A
AA
Bohn
B Paige
BP
Lawrence
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology / Q000821:virology; D019363:Cytochrome P-450 CYP1A1 / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007132:Immunoglobulin Isotypes / Q000097:blood; D009980:Influenza A virus / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000821:virology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000401:mortality; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
D000914:Antibodies, Viral; D007132:Immunoglobulin Isotypes; D000072317:Polychlorinated Dibenzodioxins; D018664:Interleukin-12; D007371:Interferon-gamma; D019363:Cytochrome P-450 CYP1A1