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：
8197360
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 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197360
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）：长期暴露于普通水污染物三氯乙烯（TCE）的浓度太低而无法引起急性毒性仍然可以促进超敏反应和自身免疫性疾病。我们已经表明，饮用水中的TCE诱导小鼠T细胞介导的自身免疫性肝炎。我们还发现，TCE降低了激活诱导的CD4+ T细胞凋亡，该过程旨在预防自身免疫性，并刺激TH1和TH17细胞的产生。 CD4+ T细胞激活诱导的细胞凋亡的普遍减少可能使人倾向于不同类型的免疫相关疾病。因此，证明常见的水污染物会引起这种作用，并描述其机制可能对人类健康具有重要意义。最近，我们表明TCE增加了称为MMP-7和促炎性细胞因子骨桥蛋白的SHEDDASE的产生。该建议将使用MRL+/+小鼠模型来测试TCE刺激MMP-7和CD4+ T细胞OPN产生的巨噬细胞/树突状细胞产生的假设，并且这两个介体共同抑制CD4+ T细胞凋亡，并促进TH1和TH17细胞的发育。它还将检验次要假设，即由于其对CD4+ T细胞凋亡的普遍作用，TCE的自身免疫性促进作用涵盖了除自身免疫性肝炎以外的其他疾病。这些假设将在以下目的中进行检验：目标1。测试TCE如何改变CD4+ T细胞子群的发育和巨噬细胞/树突状细胞活性。来自TCE处理的MRL+/+小鼠的巨噬细胞和树突状细胞将测试以生产MMP-7，以及产生Th1和Th17细胞的细胞因子。 TCE扩展了分泌OPN以及Th1-或Th17样细胞因子的活化活化（CD44HI）CD4+ T细胞的能力。 AIM 2。测试TCE如何抑制CD4+ T细胞中激活诱导的凋亡。该目标将通过测试外源MMP-7和OPN抑制未处理小鼠CD4+ T细胞激活诱导的凋亡的能力来提供“概念证明”。倒数实验将使用MMP-7和/或OPN的抗体来阻断TCE诱导的在体外CD4+ T细胞中激活诱导的凋亡的阻断。 AIM 3。使用抗原特异性CD4+ T细胞来表征TCE在体内的影响。转基因小鼠将更直接地证明TCE对体内CD4+ T细胞凋亡和效应子功能的影响，并测试除自身免疫性肝炎外，TCE的自身免疫性促进作用是否涵盖其他疾病。公共卫生相关性：CD4+ T细胞激活诱导的细胞凋亡的普遍减少可能会使个体患上许多不同类型的高敏性疾病和自身免疫性疾病。因此，证明诸如三氯乙烯之类的常见水污染物可以引起这种作用，并描述其机制可能对人类健康具有重要意义。