Stress & Enhancement of Skin Immunity: Molecular Mechani

这些研究的总体目标是阐明最近发现的在特定条件下应激可以增强皮肤免疫力的机制。我们最初报道，急性或短期应激导致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，我们使用迟发性超敏反应(DTH)作为皮肤细胞免疫的体内检测方法，研究了这种白细胞运输的功能后果。研究表明，在第一次(致敏阶段)或第二次(挑战阶段)抗原暴露之前立即经历的急性应激显著增加皮肤DTH。相反，慢性应激抑制了皮肤DTH。与这些研究一致的是，几位研究人员报道了应激诱导的DTH对不同致敏和挑战部位的不同抗原的增强作用。我们研究计划的长期目标是阐明急性和慢性应激对免疫功能的双向影响的神经内分泌和免疫介体以及健康后果。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机制。这些研究将使用野生型和基因敲除小鼠、免疫中和法、流式细胞术、免疫组织化学、原位杂交、RT-PCR和ELISA法，从生物、细胞、蛋白质和基因表达水平进行分析。将解决三个具体目标：1)确定介导应激诱导的白细胞重新分布的细胞黏附分子。2)确定介导应激诱导的DTH敏感期和攻击期增强的白细胞亚群。3)确定介导应激诱导的DTH两个阶段增强的趋化因子和细胞因子。这些研究很重要，因为应激被怀疑在许多疾病的病因中发挥作用，我们建议研究应激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。和DTH，调节免疫保护(例如对感染和癌症的抵抗力和接种疫苗后的免疫)和免疫病理(例如自身免疫、皮炎和肉芽肿疾病)的各个方面。希望这些机制的阐明将有助于生物医学治疗的发展，这些生物医学治疗旨在根据患者的临床需要，利用和个体的生理来选择性地增强(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)免疫反应。

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.