Chronic exposure to the common water pollutant trichloroethylene (TCE) at concentrations too low to cause acute toxicity can still promote hypersensitivity disorders and autoimmune disease. We have shown that TCE in drinking water induced T cell-mediated autoimmune hepatitis in mice. We also found that TCE decreased activation-induced apoptosis in CD4+ T cells, a process designed to protect against autoimmunity, and stimulates generation of both Th1 and Th17 cells. A generalized decrease in CD4+ T cell activation-induced apoptosis could predispose an individual to different types of immune-related disorders. Thus, demonstrating that a common water pollutant can cause this effect and describing the mechanism for it could have important implications for human health. Most recently we have shown that TCE increased the production of a sheddase known as MMP-7 and a pro-inflammatory cytokine known as osteopontin. This proposal will use the MRL+/+ mouse model to test the hypothesis that TCE stimulates macrophage/dendritic cell production of MMP-7 and CD4+ T cell production of OPN, and that these two mediators work together to inhibit CD4+ T cell apoptosis and promote development of Th1 and Th17 cells. It will also test the secondary hypothesis that due to its generalized effect on CD4+ T cell apoptosis the autoimmune-promoting effects of TCE encompasses other diseases besides autoimmune hepatitis. These hypotheses will be tested in the following Aims:
Aim 1. Test how TCE alters CD4+ T cell subset development and macrophage/dendritic cell activity. Macrophages and dendritic cells from TCE-treated MRL+/+ mice will be tested for production of MMP-7, as well as cytokines that generate Th1 and Th17 cells. The ability of TCE to expand activated (CD44hi) CD4+ T cells that secrete OPN as well as Th1- or Th17-like cytokines will be tested.
Aim 2. Test how TCE inhibits activation-induced apoptosis in CD4+ T cells.
This aim will provide "proof of concept" by testing the ability of exogenous MMP-7 and OPN to inhibit activation-induced apoptosis in CD4+ T cells from untreated mice. Reciprocal experiments will use antibodies for MMP-7 and/or OPN to block TCE-induced blockade of activation-induced apoptosis in CD4+ T cells in vitro.
Aim 3. Using antigen-specific CD4+ T cell to characterize the effects of TCE in vivo. Transgenic mice will be used to more directly demonstrate the effects of TCE on CD4+ T cell apoptosis and effector function in vivo, and to test whether the autoimmune-promoting effects of TCE encompasses other diseases besides autoimmune hepatitis.
A generalized decrease in CD4+ T cell activation-induced apoptosis could predispose an individual to many different types of hypersensitivity disorders and autoimmune disease. Consequently, demonstrating that a common water pollutant such as trichloroethylene can cause this effect and describing the mechanism for it could have important implications for human health.
|Gilbert, Kathleen M; Reisfeld, Brad; Zurlinden, Todd J et al. (2014) Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis. Toxicol Appl Pharmacol 279:284-93|
|Gilbert, Kathleen M; Nelson, Ashley R; Cooney, Craig A et al. (2012) Epigenetic alterations may regulate temporary reversal of CD4(+) T cell activation caused by trichloroethylene exposure. Toxicol Sci 127:169-78|
|Gilbert, Kathleen M; Rowley, Benjamin; Gomez-Acevedo, Horacio et al. (2011) Coexposure to mercury increases immunotoxicity of trichloroethylene. Toxicol Sci 119:281-92|