Fw: Chemically Induced Auto-Immune Disorders

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From: " ilena rose " <ilena@...>

Sent: Wednesday, May 16, 2001 9:14 PM

Subject: Chemically Induced Auto-Immune Disorders

> ~~~ thanks much rosemarie ~~~

>

> 1999 Progress Report: Mechanism(s) of Chloroethylene-Induced Autoimmunity

>

>

> EPA Grant Number: R826409

>

> Progress Report: Mechanism(s) of Chloroethylene-Induced Autoimmunity

>

> Investigators: Kathleen M. Gilbert, Neil R. Pumford

>

> Institution: University of Arkansas for Medical Sciences, University of

> Arkansas, Fayetteville

>

> EPA Project Officer: Reese

>

> Project Period: March 25, 1998 March 24, 2001

>

> Research Category: Exploratory Research Human Health

>

> Objective(s) of the Research Project:

>

> 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/Accomplishments:

>

> 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).

>

>

> Publications/Presentations:

>

> JM, Gilbert KM, Pumford NR. Cytochrome P450 2E1 metabolism of

> trichloroethylene accelerates an autoimmune response in MRL+/+ mice.

> Toxicological Sciences 1999;48(1-S):792 (outstanding graduate student

> presentation in immunotoxicology sward presented by immunotoxicology

> specialty section).

>

> JM, Blossom SJ, 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.

>

> Gilbert KM, JM, Pumford NR. Trichloroethylene activates CD4+ T

> cells: potential role in an autoimmune response. Drug Metabolism Reviews

> 1999;31(4):901-916.

>

> JM, Gilbert KM, Pumford NR. Inhibition of CYP2E1 reverses CD4+ T

> cell alterations in trichloroethylene-treated MRL+/+ mice. Toxicological

> Sciences 2000;54:384-389.

>

> JM, Gilbert KM, Lamps LW, Pumford NR. CD4+ T cell activation and

> induction of autoimmune hepatitis following trichloroethylene treatment in

> MRL+/+ mice. Toxicological Sciences 2000;57:345-352.

>

> Pumford NR. Immunochemical approaches used to identify and characterize

> protein adducts associated with xenobiotic-induced toxicities. In:

> Proceedings of the invited symposium presentation at the ISSX Annual

North

> American Meeting, Volume 15, 27, 1999.

>

> Pumford NR. Oxidative stress and endothelial cell damage in

> autoimmune-prone MRL+/+ mice following trichloroethylene treatment.

> Presented at the Annual Meeting of the Society of Toxicology, San

> Francisco, CA, 2001.

>

>

> 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).

>

> Supplemental Keywords: volatile organic compounds, VOC, intermediates,

> metabolism, human health, genetic pre-disposition, sensitive populations,

> susceptibility.

>

>

>