Stress & Enhancement of Skin Immunity: Molecular Mechani

压力

• 批准号: 6511425
• 负责人: FIRDAUS S DHABHAR
• 金额: $ 29.49万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511425
• 关键词: T lymphocyte; cell adhesion molecules; cell migration; cellular immunity; chemokine; delayed hypersensitivity; enzyme linked immunosorbent assay; flow cytometry; gene expression; gene targeting; genetically modified animals; glucocorticoids; granulocyte; immunocytochemistry; immunologic memory; in situ hybridization; laboratory mouse; leukocyte activation /transformation; macrophage; psychoneuroimmunology; restraint; skin; stress

The overall goal of these studies is to elucidate the mechanisms mediating the recent finding that under certain conditions stress can enhance skin immunity. We initially reported that acute of short-duration stress induces a redistribution of immune cells from the blood to organs such as the skin. Since the skin is the body's first line of defense, we examined the functional consequences of this leukocyte trafficking using the delayed type hypersensitivity (DTH) response as an in vivo assay for skin cell mediated immunity. Studies showed that acute stress experienced immediately before primary ( sensitization phase) or secondary (challenge phase) antigen exposure significantly enhanced skin DTH. In contrast, chronic stress suppressed skin DTH. In agreement with these studies, several investigators have reported stress-induced enhancement of DTH to different antigens administered to different sites of sensitization and challenge. The long- term objective of our research program is to elucidate the neuroendocrine and immune mediators and health consequences of the bi-directional effects of acute versus chronic stress on immune function. The overall goal of the proposed studies is to elucidate the mechanisms mediating the effects of acute stress on leukocyte trafficking and skin immunity. These studies will use wild type and gene knockout mice, immunoneutralization, flow cytometry, immunohistochemistry, in situ hybridization, RT-PCR, and ELISA to conduct analyses at the level of the organism, cell, protein, and gene expression. Three specific aims will be addressed: 1)Identify cell adhesion molecules that mediate the stress-induced redistribution of leukocytes. 2) Identify leukocyte subpopulations that mediate a stress-induced enhancement of the sensitization and challenge phases of DTH. 3) Identify chemokines and cytokines that mediate a stress-induced enhancement of both phases of DTH. These studies are important because stress is suspected to play a role in the etiology of many diseases and we propose to study the effects of stress on two important immune parameters: Leukocyte trafficking, which is crucial for the surveillance and effector functions of the immune system. And DTH, which mediates aspects of immunoprotection (e.g. resistance to infections and cancer and post-vaccination immunity) and immunopathology (e.g. autoimmune, dermatitis, and granulomatous disorders). It is hoped that the elucidation of mechanisms such as those proposed here will facilitate the development of biomedical treatments designed to harness and individual's physiology to selectively enhance (during surgery, wound healing, infections, or cancer) or suppress (during autoimmune or inflammatory disorders) an immune response depending on the clinical needs to the patient.

这些研究的总体目标是阐明介导最近发现的机制，即在某些条件下，压力可以增强皮肤免疫力。 我们最初报道，急性或短期应激诱导免疫细胞从血液重新分布到皮肤等器官。 由于皮肤是人体的第一道防线，我们研究了这种白细胞运输的功能后果，使用迟发型超敏反应（DTH）作为皮肤细胞介导的免疫力的体内测定。 研究表明，在初次（致敏阶段）或二次（激发阶段）抗原暴露前即刻经历的急性应激显著增强皮肤DTH。 相反，慢性应激抑制皮肤DTH。 与这些研究一致，一些研究者报道了对不同致敏和激发部位施用不同抗原的应激诱导的DTH增强。 我们研究计划的长期目标是阐明神经内分泌和免疫介质以及急性与慢性应激对免疫功能的双向影响的健康后果。拟议研究的总体目标是阐明急性应激对白细胞运输和皮肤免疫的影响的介导机制。 这些研究将使用野生型和基因敲除小鼠、免疫中和、流式细胞术、免疫组织化学、原位杂交、RT-PCR和ELISA在生物体、细胞、蛋白质和基因表达水平上进行分析。 三个具体的目标将被解决：1）确定细胞粘附分子介导的压力诱导的白细胞再分布。 2)识别介导应激诱导的DTH致敏和激发阶段增强的白细胞亚群。 3)确定趋化因子和细胞因子介导的应激诱导增强的两个阶段的DTH。这些研究很重要，因为压力被怀疑在许多疾病的病因学中起作用，我们建议研究压力对两个重要免疫参数的影响：白细胞运输，这对免疫系统的监视和效应功能至关重要。以及DTH，其介导免疫保护（例如对感染和癌症的抗性以及疫苗接种后免疫）和免疫病理学（例如自身免疫性、皮炎和肉芽肿性病症）的方面。 希望阐明机制，如本文提出的那些机制，将促进生物医学治疗的发展，这些治疗旨在利用个体的生理学，根据患者的临床需要，选择性地增强（在手术、伤口愈合、感染或癌症期间）或抑制（在自身免疫或炎症性疾病期间）免疫应答。