Grantee Research Project Results
1999 Progress Report: Mechanism(s) of Chloroethylene-Induced Autoimmunity
EPA Grant Number: R826409Title: Mechanism(s) of Chloroethylene-Induced Autoimmunity
Investigators: Pumford, Neil R. , Gilbert, Kathleen M.
Institution: University of Arkansas for Medical Sciences , University of Arkansas
EPA Project Officer: Aja, Hayley
Project Period: March 25, 1998 through March 24, 2001
Project Period Covered by this Report: March 25, 1998 through March 24, 1999
Project Amount: $374,384
RFA: Exploratory Research - Human Health (1997) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The overall estimation for the number of people afflicted with autoimmune diseases in the United States is over 8.5 million or approximately 1 in every 31 Americans. The development of autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma) is believed to be multifactorial, involving both genetic and environmental components. Chemical exposures may be a major environmental influence on the development of autoimmune diseases. There is good evidence supporting an association of chlorinated ethylenes with life-threatening autoimmune disorders such as systemic lupus erythematosus and scleroderma. However, the mechanisms by which chlorinated ethylenes cause autoimmunity are unknown.We hypothesize that chlorinated ethylenes are metabolized to reactive intermediates that initiate an autoimmune response. The autoimmune response involves the activation of CD4+ T-cells that are stimulated by either a specific response against the chlorinated ethylene-modified proteins or a non-specific response initiated through the release of serum factors, such as cytokines, growth factors, or unidentified factors. Either pathway will result in the activation of T-cells, which in turn can lead to the development of inflammation.
Progress Summary:
Our initial studies in MRL+/+ mice demonstrated that trichloroethylene accelerated the innate autoimmune response in these mice (Immunopharmacology 2000;46(2):123-137). Activation of T cells was shown to be important in this acceleration as indicated by an increase in the T cell activation marker CD44. The activated T cells produced an inflammatory cytokine profile. There was a dose-dependent increase in anti-nuclear antibodies, an autoimmune marker.In the next experiment we used the cytochrome P450 inhibitor, diallyl sulfide, to completely blocked covalent binding of trichloroethylene to protein used as an indicator of metabolic activation. The lack of metabolic activation was accompanied by a decrease in T cells activation and the production of inflammatory cytokines (Toxicological Sciences 2000;54:384-389).
In our most recent series of experiments, we used lower, more environmentally relevant, doses hoping to activate the immune system similar to that found with higher doses (Toxicological Sciences 2000;57:345-352). Metabolic activation of trichloroethylene occurred following exposure and the covalently modified protein adducts were localized to the central region of the liver. Trichloroethylene treatment activated CD4+ T cell to produce Th1-like or inflammatory cytokine profile. There was a significant increase in ANA, a measure of an autoimmune response, following treatment with trichloroethylene. Following 32 weeks of trichloroethylene treatment there was a massive mononuclear infiltration localized to the portal region of the liver with a significant increase in a liver function tests and pathological damage all of which are common features of autoimmune hepatitis. This is the first report in which trichloroethylene induced the clinical signs of autoimmune hepatitis in an animal model.
We have hypothesized in a review article about possible mechanisms for the T cell activation associated with the trichloroethylene-induced autoimmunity preliminary evidence to support our hypothesis (Drug Metabolism Reviews 1999;31(4):901-916).
We also developed a biomarker for environmental exposure to trichloroethylene correlates with markers of autoimmune disease such as ANA. We developed an ELISA to detect antibodies to the major trichloroethylene-protein adducts (dichloroacetyl-cytochrome P450 2E1). Using serum from a population exposed to trichloroethylene and from a comparable non-exposed population we found no correlation with trichloroethylene-protein adducts and the autoimmune marker ANA (p = 0.07; unpublished results).
Future Activities:
Our present experiments are focused on determining possible mechanisms for the polyclonal activation of T cells. We also are continuing to develop a biomarker for detecting an association with trichloroethylene and an autoimmune response in humans. We also are investigating downstream events such as activation of macrophages and endothelial cells (Society of Toxicology platform presentation 2001).Journal Articles on this Report : 3 Displayed | Download in RIS Format
Other project views: | All 21 publications | 6 publications in selected types | All 6 journal articles |
---|
Type | Citation | ||
---|---|---|---|
|
Gilbert KM, Griffin JM, Pumford NR. Trichloroethylene activates CD4+ T cells: potential role in an autoimmune response. Drug Metabolism Reviews 1999;31(4):901-916. |
R826409 (1999) R826409 (Final) |
Exit |
|
Griffin JM, Gilbert KM, Pumford NR. Inhibition of CYP2E1 reverses CD4+ T cell alterations in trichloroethylene-treated MRL+/+ mice. Toxicological Sciences 2000;54(2):384-389. |
R826409 (1999) R826409 (Final) |
Exit Exit |
|
Griffin JM, Blossom SJ, Jackson SK, Gilbert KM, Pumford NR. Trichloroethylene accelerates an autoimmune response in association with Th1 T-cell activation in MRL+/+ mice. Immunopharmacology, 2000;46(2):123-137. |
R826409 (1999) R826409 (Final) |
not available |
Supplemental Keywords:
volatile organic compounds, VOC, intermediates, metabolism, human health, genetic pre-disposition, sensitive populations, susceptibility., RFA, Health, Scientific Discipline, Toxics, Waste, Genetics, Environmental Chemistry, Health Risk Assessment, VOCs, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Disease & Cumulative Effects, Hazardous Waste, Biochemistry, genetic susceptability, Hazardous, 33/50, health effects, sensitive populations, biomarkers, chloroethylene autoimmunity, effects assessment, cytochrome P450, lupus erythematosus, scleroderma, chlorinated ethylenes, cytokines, gene-environment interaction, Tetrachloroethylene, exposure, genetic predisposition, Lymphocytes, Trichloroethylene, human exposure, rheumatoid arthritis, chemical releases, hazardous chemicals, environmentally caused disease, human susceptibility, metabolism, chloroethylenes, air emissions, Vinyl chloride, exposure assessment, groundwater, immune response, autoimmune diseases, occupational exposure, autoimmunity, air contaminant exposureProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.