TCDD-treated B Cells Modulate T Effector and T Regulatory Function in EAE

TCDD 处理的 B 细胞调节 EAE 中的 T 效应子和 T 调节功能

基本信息

批准号：
9231554
负责人：
Barbara Lee-Faubert Kaplan
金额：
$ 43.65万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231554
关键词：
Animal Model Apoptosis Aryl Hydrocarbon Receptor Attenuated Autoimmune Diseases Autoimmune Process B-Lymphocytes CD19 gene CD4 Positive T Lymphocytes Cell Communication Cell Maintenance Cell physiology Cells Chronic Data Data Analyses Dioxins Disease Dose Effector Cell Environmental Pollution Experimental Autoimmune Encephalomyelitis Experimental Designs Exposure to FOXP3 gene Genes Glucocorticoids Goals Human IL2RA gene Immune Immunity Immunosuppression In Vitro Inflammatory Information Dissemination Interferon Type II Lead Ligands Lymphocyte Mediating Modeling Multiple Sclerosis Mus Neuraxis Oral Play Population Production Receptor Signaling Regulatory T-Lymphocyte Research Proposals Role Spinal Cord Spleen Systemic disease T cell response T-Lymphocyte TNF gene Testing Th1 Cells Therapeutic Training Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Necrosis Factor Receptor aryl hydrocarbon receptor ligand attenuation cytokine extracellular immunotoxicity lymph nodes receptor receptor expression receptor function response systemic toxicity undergraduate student

项目摘要

ABSTRACT Determination of the mechanisms by which 2,3,78-tetrachlorodibenzo-p-dioxin (TCDD) suppress immunity are important for several reasons. First, there is potential for chronic low dose TCDD exposure to produce immunotoxicity and render populations susceptible to disease. Second, TCDD can be used as a model ligand to understand aryl hydrocarbon receptor (AHR) signaling in lymphocytes. Finally, identification of AHR ligands that produce less systemic toxicity than TCDD might lead to useful therapeutics for autoimmune and inflammatory diseases. We have established that subchronic low dose TCDD produced suppression of effector T cell function and attenuation of disease in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We determined that TCDD not only suppressed T cell cytokine production but also induced regulatory T cells (Tregs). The goal of this research proposal is to determine the effect of TCDD on regulatory B cell populations in EAE and assess the contribution that TCDD-treated regulatory B cells make to TCDD-mediated alterations in T cell function. We will test the hypothesis that the mechanism by which TCDD suppresses EAE involves induction of regulatory cells, which control effector and regulatory T cell responses. Our first specific aim (SA) will be to characterize the effects of TCDD on regulatory B cell populations with a focus on regulatory B cells that can alter T cell function through cell-cell interactions. Our second SA is to determine the role that TCDD-treated B regulatory cells have on TH1, TH2 and TH17 effector T cells. Our third SA is to determine the role that TCDD-treated B regulatory cells have on Tregs. We expect that the results from these studies will establish that TCDD can induce regulatory B cell populations that contribute to either suppression of effector T cell responses or induction of Tregs. The studies will also provide a comparison of the ability of TCDD to induce regulatory B cells in mouse and human. Another critical aspect of this research proposal is that several undergraduate students will be involved over the 3-year period and receive training in hypothesis testing, experimental design, data analysis and interpretation, and effective dissemination of results in both oral and written form.

抽象的确定 2,3,78-四氯二苯并-对二恶英 (TCDD) 抑制免疫力的机制出于多种原因，它很重要。首先，长期低剂量 TCDD 暴露可能会产生免疫毒性并使人群易患疾病。二、TCDD可作为模型配体了解淋巴细胞中的芳烃受体 (AHR) 信号传导。最后，AHR配体的鉴定比 TCDD 产生的全身毒性更小，可能会成为治疗自身免疫性疾病的有用疗法。炎症性疾病。我们已经确定，亚慢性低剂量 TCDD 会抑制实验性自身免疫性脑脊髓炎 (EAE) 中的效应 T 细胞功能和疾病减弱多发性硬化症动物模型。我们确定 TCDD 不仅抑制 T 细胞细胞因子的产生还诱导调节性 T 细胞 (Treg)。本研究计划的目标是确定以下效果： TCDD 对 EAE 中调节性 B 细胞群的影响，并评估 TCDD 处理的调节性 B 细胞的贡献 TCDD 介导的 T 细胞功能改变。我们将检验该机制的假设 TCDD 抑制 EAE 涉及调节细胞的诱导，调节细胞控制效应子和调节性 T 细胞反应。我们的第一个具体目标 (SA) 是描述 TCDD 对调节性 B 细胞群，重点关注可通过细胞间改变 T 细胞功能的调节性 B 细胞互动。我们的第二个 SA 是确定 TCDD 处理的 B 调节细胞对 TH1、TH2 的作用和 TH17 效应 T 细胞。我们的第三个 SA 是确定经 TCDD 处理的 B 调节细胞对特雷格斯。我们期望这些研究的结果将证实 TCDD 可以诱导调节性 B 细胞有助于抑制效应 T 细胞反应或诱导 Tregs 的群体。研究还将提供 TCDD 在小鼠和人类中诱导调节性 B 细胞的能力的比较。这项研究计划的另一个重要方面是，多名本科生将参与其中 3年期间，接受假设检验、实验设计、数据分析和解释，并以口头和书面形式有效传播结果。