CD4(+) T-cell activation and induction of autoimmune hepatitis following trichloroethylene treatment in MRL +/+ mice

Exposure to relatively high levels of trichloroethylene has recently been s hown to accelerate the development of an autoimmune response in the autoimm une prone MRL+/+ mice. The trichloroethylene-induced autoimmune response wa s associated with an increase in activated CD4(+) T cells, producing Th-1-l ike 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 th is accelerated autoimmune response. In addition, histological studies were performed to determine if trichloroethylene was capable of producing pathol ogical 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 f or 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 indicate d that trichloroethylene accelerated the innate autoimmune response in the MRL+/+ mice. There was a dose-related increase in the percentage of activat ed CD4(+) T cells in both the spleens and lymph nodes of mice treated for 3 2 weeks with trichloroethylene when compared to controls. CD4(+) T cells is olated from MRL+/+ mice after either 4 or 32 weeks of treatment with trichl oroethylene secreted inflammatory or Th-1-like cytokines. Following 32 week s of trichloroethylene treatment, there was a significant increase in hepat ic mononuclear infiltration localized to the portal region, a type of hepat ic infiltration consistent with autoimmune hepatitis. Taken collectively, t hese data suggest that exposure to occupationally relevant concentrations o f trichloroethylene can accelerate an autoimmune response and can lead to a utoimmune disease. The mechanism of this autoimmunity appears to involve, a t least in part, activated CD4(+) T cells that then produced inflammatory c ytokines.