Toxicological Sciences 57, 345-352 (2000)
Copyright © 2000 by the Society of Toxicology
Systems Toxicology |
CD4+ T-Cell Activation and Induction of Autoimmune Hepatitis following Trichloroethylene Treatment in MRL+/+ Mice
* Department of Pharmacology and Toxicology,
Department of Microbiology and Immunology, and
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; and
§ Division of Agriculture, University of Arkansas, Fayetteville, Arkansas 72701
Exposure to relatively high levels of trichloroethylene has recently been shown to accelerate the development of an autoimmune response in the autoimmune prone MRL+/+ mice. The trichloroethylene-induced autoimmune response was associated with an increase in activated CD4+ T cells, producing Th1-like cytokines. The present study was conducted to determine whether lower, more occupationally relevant doses of trichloroethylene could also promote autoimmunity, in MRL+/+ mice, and if so, to investigate the mechanism of this accelerated autoimmune response. In addition, histological studies were performed to determine if trichloroethylene was capable of producing pathological markers consistent with an autoimmune disease. Trichloroethylene was administered to mice in the drinking water at 0, 0.1, 0.5, and 2.5 mg/ml for 4 and 32 weeks. There was a significant increase above controls in serum antinuclear antibody (ANA) levels following 4 weeks of both 0.1 and 0.5 mg/kg/day of trichloroethylene. After 32 weeks of treatment, ANA levels were elevated and equal in all groups. The kinetics of the ANA response indicated that trichloroethylene accelerated the innate autoimmune response in the MRL+/+ mice. There was a dose-related increase in the percentage of activated CD4+ T cells in both the spleens and lymph nodes of mice treated for 32 weeks with trichloroethylene when compared to controls. CD4+ T cells isolated from MRL+/+ mice after either 4 or 32 weeks of treatment with trichloroethylene secreted inflammatory or Th1-like cytokines. Following 32 weeks of trichloroethylene treatment, there was a significant increase in hepatic mononuclear infiltration localized to the portal region, a type of hepatic infiltration consistent with autoimmune hepatitis. Taken collectively, these data suggest that exposure to occupationally relevant concentrations of trichloroethylene can accelerate an autoimmune response and can lead to autoimmune disease. The mechanism of this autoimmunity appears to involve, at least in part, activated CD4+ T cells that then produced inflammatory cytokines.
Key Words: antinuclear antibodies (ANA); inflammatory cytokines; dose-related response; hepatic mononuclear infiltration; scleroderma; systemic lupus erythematosus.
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