Consequences of AhR Activation in Dendritic Cells

树突状细胞中 AhR 激活的后果

• 批准号: 7039381
• 负责人: David M Shepherd
• 金额: $ 33.32万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039381
• 关键词: CD4 molecule; CD95 molecule; T lymphocyte; apoptosis; aromatic hydrocarbon receptor; cell cycle; dendritic cells; dioxins; environmental exposure; environmental toxicology; flow cytometry; gene expression; genetic regulatory element; genetically modified animals; immunosuppression; immunotoxicity; laboratory mouse; leukocyte activation /transformation; ligands; nuclear factor kappa beta; receptor expression; transfection

DESCRIPTION (provided by applicant): The Aryl hydrocarbon receptor (AhR) mediates the toxic effects of a broad class of environmental contaminants, the halogenated aromatic hydrocarbons. Moreover, the immune system is a very sensitive target of the prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-induced immune dysfunction is characterized by profound suppression of T cell-mediated immunity and increased susceptibility to disease. Dendritic cells (DC) that function to induce the activation, expansion and differentiation of T cells are postulated to be direct targets of TCDD. DC aberrantly express critical costimulatory molecules and undergo premature deletion from immune tissues following AhR activation by TCDD. Therefore, we hypothesize AhR activation in DC causes defects in their activation and/or survival and ultimately contributes to the suppression of adaptive immunity. The focus of this laboratory is to understand the cellular and molecular basis for the potent immune suppression induced by AhR ligands, while the primary objective of this proposal is to determine the mechanisms underlying TCDD-induced suppression of DC functions. These objectives will be determined by the following four Specific Aims: (1) to define the role of AhR activation in the fate and function of DC; (2) to determine if the effects of AhR activation in DC are mediated exclusively via the Dioxin Response Element (ORE); and (3) to investigate the involvement of the Fas/Fas ligand pathway and cell cycle perturbation in AhR-mediated DC death. The research proposed in this application will have significant, positive effects on human health. This work will advance our basic understanding of DC interactions with antigen-specific T cells. It will define mechanisms of xenobiotic-induced immunotoxicity, and may identify novel therapeutic approaches to generate tolerogenic DC.

描述（由申请人提供）：芳烃受体（AhR）介导一类广泛的环境污染物（卤代芳烃）的毒性作用。此外，免疫系统是原型AhR配体2，3，7，8-四氯二苯并-p-二恶英（TCDD）的非常敏感的靶标。TCDD引起的免疫功能障碍的特点是严重抑制T细胞介导的免疫和增加对疾病的易感性。树突状细胞（DC）的功能是诱导T细胞的活化、扩增和分化，被认为是TCDD的直接靶点。DC异常表达关键的共刺激分子，并在TCDD激活AhR后从免疫组织中过早缺失。因此，我们假设DC中的AhR激活导致其激活和/或存活缺陷，并最终导致适应性免疫的抑制。该实验室的重点是了解AhR配体诱导的有效免疫抑制的细胞和分子基础，而本提案的主要目标是确定TCDD诱导的DC功能抑制的机制。这些目标将由以下四个具体目标确定：（1）确定AhR活化在DC的命运和功能中的作用;（2）确定DC中AhR活化的作用是否仅通过二恶英反应元件（ORE）介导;和（3）研究Fas/Fas配体途径和细胞周期扰动在AhR介导的DC死亡中的参与。本申请中提出的研究将对人类健康产生重大的积极影响。这项工作将推进我们对DC与抗原特异性T细胞相互作用的基本理解。它将确定外源性诱导的免疫毒性的机制，并可能确定新的治疗方法，以产生耐受性DC。