Determining how trichloroethylene alters CD4+ T cell function

确定三氯乙烯如何改变 CD4 T 细胞功能

基本信息

批准号：
8011739
负责人：
KATHLEEN M GILBERT
金额：
$ 32.97万
依托单位：
ARKANSAS CHILDREN'S HOSPITAL RES INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-07 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011739
关键词：
Acute Adoptive Transfer Affect Antibodies Antigens Apoptosis Autoimmune Diseases Autoimmune Hepatitis Autoimmune Process Autoimmunity CD4 Positive T Lymphocytes Cell physiology Cell surface Cells Chemicals Chronic Dendritic Cells Development Disease Environmental Pollutants Evaluation Exposure to Future Generations Health Human Hyperactive behavior Hypersensitivity Immune Immune system In Vitro Individual Inflammation Inflammatory Interferons Intervention Matrilysin Mediating Mediator of activation protein Metalloproteases Mus Organic solvent product Pathway interactions Population Process Production Relative (related person)Research T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Toxic effect Transgenic Mice Transgenic Organisms Trichloroethylene Water Pollutants Work Workplace autoreactive T cell cytokine design drinking water exposed human population in vivo inhibitor/antagonist macrophage mathematical model mouse model osteopontin prevent public health relevance remediation research study

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：长期接触常见水污染物三氯乙烯（TCE），其浓度过低而不会引起急性毒性，但仍会促进过敏性疾病和自身免疫性疾病。我们已经证明饮用水中的 TCE 会诱导小鼠 T 细胞介导的自身免疫性肝炎。我们还发现 TCE 减少了 CD4+ T 细胞中激活诱导的细胞凋亡（这一过程旨在防止自身免疫），并刺激 Th1 和 Th17 细胞的生成。 CD4+ T 细胞活化诱导的细胞凋亡普遍减少可能会使个体易患不同类型的免疫相关疾病。因此，证明一种常见的水污染物可以引起这种效应并描述其机制可能对人类健康产生重要影响。最近，我们发现 TCE 增加了一种称为 MMP-7 的脱落酶和一种称为骨桥蛋白的促炎细胞因子的产生。该提案将使用MRL+/+小鼠模型来检验TCE刺激巨噬细胞/树突状细胞产生MMP-7和CD4+ T细胞产生OPN，并且这两种介质共同作用抑制CD4+ T细胞凋亡并促进发育的假设Th1 和 Th17 细胞。它还将检验第二个假设，即由于 TCE 对 CD4+ T 细胞凋亡的普遍影响，TCE 的自身免疫促进作用还涵盖除自身免疫性肝炎之外的其他疾病。这些假设将在以下目标中进行测试：目标 1. 测试 TCE 如何改变 CD4+ T 细胞亚群发育和巨噬细胞/树突状细胞活性。将测试 TCE 治疗的 MRL+/+ 小鼠的巨噬细胞和树突状细胞是否产生 MMP-7，以及产生 Th1 和 Th17 细胞的细胞因子。将测试 TCE 扩增分泌 OPN 以及 Th1 或 Th17 样细胞因子的活化 (CD44hi) CD4+ T 细胞的能力。目标 2. 测试 TCE 如何抑制激活诱导的 CD4+ T 细胞凋亡。这一目标将通过测试外源 MMP-7 和 OPN 抑制未治疗小鼠 CD4+ T 细胞激活诱导的细胞凋亡的能力来提供“概念证明”。交互实验将使用 MMP-7 和/或 OPN 抗体来阻断 TCE 诱导的体外 CD4+ T 细胞活化诱导的细胞凋亡。目标 3. 使用抗原特异性 CD4+ T 细胞来表征 TCE 的体内作用。转基因小鼠将用于更直接地证明TCE对CD4+T细胞凋亡和体内效应功能的影响，并测试TCE的自身免疫促进作用是否涵盖自身免疫性肝炎以外的其他疾病。公共健康相关性：CD4+ T 细胞活化诱导的细胞凋亡普遍减少可能会使个体易患多种不同类型的过敏性疾病和自身免疫性疾病。因此，证明三氯乙烯等常见水污染物可以引起这种效应并描述其机制可能对人类健康产生重要影响。