title: Correlation between chemical suppression of natural killer cell activity in mice and susceptibility to cytomegalovirus: rationale for applying murine cytomegalovirus as a host resistance model and for interpreting immunotoxicity testing in terms of risk of disease.
abstract: The purpose of this study was to determine the relationship between chemical suppression of natural killer (NK) cell activity in mice and chemical effects on susceptibility to murine cytomegalovirus (MCMV) infection. The goal was to provide a rational basis for applying MCMV as a host resistance model for immunotoxicity testing and to provide risk assessors some guidance in relating suppression of NK cell activity to enhanced risk of disease. Data from studies with eight chemicals administered in various doses and by various routes were evaluated, and a significant correlation was observed between chemical suppression of virus-augmented NK cell activity and increased mortality due to MCMV infection. In contrast, effects of the same chemical treatments on spontaneous NK cell activity (i.e., basal activity in uninfected mice) did not correlate with effects of these chemicals on mortality due to MCMV. Although chemicals that suppressed spontaneous NK cell activity enhanced infection, the converse was not always true--that is, increased susceptibility to infection and suppression of virus-augmented NK cell activity were observed on three occasions when spontaneous NK cell activity was unaffected. This latter phenomenon plus the fact that for two chemicals spontaneous NK was suppressed at concentrations twofold below that which affected mortality appear to account for the poor statistical correlation. Nevertheless, the data indicate that MCMV is a useful host resistance model to be applied in immunotoxicity testing when suppression of NK cell activity has been demonstrated. However, virus-augmented activity may be a better indicator than spontaneous activity. The data also indicated that suppression of NK cell activity is predictive of increased susceptibility to infection and hence provides qualitative guidance (hazard identification) to risk assessors.
authors.affiliation: Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
authors.forename: M K
authors.initials: MK
authors.lastname: Selgrade
authors.forename: M J
authors.initials: MJ
authors.lastname: Daniels
authors.forename: J H
authors.initials: JH
authors.lastname: Dean
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D002104:Cadmium / Q000633:toxicity; D019256:Cadmium Chloride; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity; D003520:Cyclophosphamide / Q000633:toxicity; D016572:Cyclosporine / Q000633:toxicity; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004198:Disease Susceptibility; D005260:Female; D005677:G(M1) Ganglioside / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D009532:Nickel / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D013047:Specific Pathogen-Free Organisms; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D002712:Chlorides; D007166:Immunosuppressive Agents; D000072317:Polychlorinated Dibenzodioxins; D002104:Cadmium; D001564:Benzo(a)pyrene; D005677:G(M1) Ganglioside; D015127:9,10-Dimethyl-1,2-benzanthracene; C022838:nickel chloride; C018835:asialo GM1 ganglioside; D009532:Nickel; D016572:Cyclosporine; D003520:Cyclophosphamide; D019256:Cadmium Chloride; D013755:Tetradecanoylphorbol Acetate