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

• 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
• 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

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.

摘要 确定2，3，78-四氯二苯并对二恶英（TCDD）抑制免疫的机制， 重要的原因有几个。首先，慢性低剂量TCDD暴露有可能产生 免疫毒性和使人群易受疾病影响。第二，TCDD可用作模型配体 了解淋巴细胞中的芳烃受体（AHR）信号。最后，AHR配体的鉴定 产生比TCDD更少的全身毒性可能导致有用的治疗自身免疫性疾病， 炎症性疾病。我们已经确定，亚慢性低剂量TCDD产生抑制， 实验性自身免疫性脑脊髓炎（EAE）中效应T细胞功能和疾病减轻， 多发性硬化症的动物模型。我们确定TCDD不仅抑制T细胞细胞因子的产生， 而且还诱导调节性T细胞（T细胞）。这项研究的目的是确定 TCDD对EAE中调节性B细胞群的影响，并评估TCDD治疗的调节性B细胞群的作用。 细胞对TCDD介导的T细胞功能的改变。我们将检验这个假设， TCDD抑制EAE的机制包括诱导调节细胞，这些细胞控制效应细胞， 调节性T细胞反应。我们的第一个具体目标（SA）将是描述TCDD对 调节性B细胞群，重点是调节性B细胞，其可以通过细胞间相互作用改变T细胞功能， 交互.我们的第二个SA是确定TCDD处理的B调节细胞对TH 1、TH 2 和TH 17效应T细胞。我们的第三个SA是确定TCDD处理的B调节细胞在TCDD治疗后的细胞凋亡中的作用。 你好我们期望这些研究的结果将确定TCDD可以诱导调节性B细胞 有助于抑制效应T细胞应答或诱导T细胞活化的细胞群。研究 还将提供TCDD诱导小鼠和人类调节性B细胞的能力的比较。 这项研究计划的另一个重要方面是，几个本科生将参与超过 并接受假设检验、实验设计、数据分析和 口译和以口头和书面形式有效传播成果。