Determining how trichloroethylene alters CD4+ T cell function

确定三氯乙烯如何改变 CD4 T 细胞功能

• 批准号: 7792667
• 负责人: KATHLEEN M GILBERT
• 金额: $ 33.17万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 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/7792667
• 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

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)：长期暴露在浓度太低而不会造成急性毒性的常见水污染物三氯乙烯(TCE)中，仍会导致过敏障碍和自身免疫性疾病。我们已经证明饮用水中的三氯乙烯可诱导小鼠T细胞介导的自身免疫性肝炎。我们还发现，TCE减少了激活诱导的CD4+T细胞的凋亡，这是一个旨在保护自身免疫的过程，并刺激Th1和Th17细胞的产生。CD4+T细胞活化诱导的细胞凋亡的普遍减少可能使个人容易患上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影响，并描述其机制，可能对人类健康具有重要意义。最近，我们发现三氯乙烯增加了一种称为基质金属蛋白酶-7的脱落酶和一种称为骨桥蛋白的促炎细胞因子的产生。这项建议将使用MRL+/+小鼠模型来验证TCE刺激巨噬细胞/树突状细胞产生MMP-7和OPN产生CD4+T细胞的假设，并且这两种介质共同作用抑制CD4+T细胞的凋亡，促进Th1和Th17细胞的发育。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涵盖了除自身免疫性肝炎以外的其他疾病。这些假说将在以下目标进行验证：目的1.测试TCE如何改变CD4+T细胞亚群的发育和巨噬细胞/树突状细胞的活性。来自TCE处理的MRL+/+小鼠的巨噬细胞和树突状细胞将被测试产生基质金属蛋白酶-7，以及产生Th1和Th17细胞的细胞因子。将测试TCE扩增激活的(CD44hi)CD4+T细胞的能力，这些细胞分泌OPN以及Th1或Th17样细胞因子。目的：检测TCE对活化诱导的CD4+T细胞凋亡的抑制作用。这一目的将通过测试外源性基质金属蛋白酶-7和骨桥蛋白抑制未经治疗的小鼠的CD4+T细胞活化诱导的凋亡的能力来提供“概念证明”。互惠实验将使用抗基质金属蛋白酶-7和/或骨桥蛋白的抗体来阻断TCE诱导的体外激活诱导的CD4+T细胞的凋亡。目的3.用抗原特异性的CD4+T细胞研究三氯乙烯的体内效应。转基因小鼠将被用来更直接地展示TCE对体内CD4+T细胞凋亡和效应器功能的影响，并测试TCE的自身免疫促进作用是否包括除自身免疫性肝炎以外的其他疾病。 公共卫生相关性：由CD4+T细胞激活诱导的细胞凋亡的普遍减少可能使个人易患许多不同类型的超敏反应障碍和自身免疫性疾病。因此，证明一种常见的水污染物，如三氯乙烯，可以引起这种影响，并描述其机制，可能对人类健康有重要的影响。