A mechanism of metal-mediated immunosuppression

金属介导的免疫抑制机制

• 批准号: 7058332
• 负责人: MICHAEL A LYNES
• 金额: $ 30.89万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058332
• 关键词: antioxidants; biological signal transduction; cadmium; cations; environmental exposure; environmental toxicology; enzyme linked immunosorbent assay; flow cytometry; free radical oxygen; gene expression; genetically modified animals; immunosuppression; immunosuppressive; laboratory mouse; leukocytes; metallothionein; transcription factor; western blottings

DESCRIPTION (provided by applicant): Heavy metal cations such as cadmium are widely found in the environment and can act as potent immunosuppressive agents. One of the biological responses to many immunosuppressive toxicants is the production of stress response proteins. Metallothionein (MT) is an intriguing example of this group of proteins, and plays several critical roles in cellular homeostasis. MT acts as a reservoir of essential metals, as a potent anti-oxidant, as a protein that can sequester toxic heavy metals and as a regulator of several transcription factors. These functions implicate MT in metal-mediated immunomodulation. We have shown that MT can significantly influence immune functions in vivo and in vitro. The fundamental premise of this proposal is that a functional immune response exists in the context of an optimum level of MT. When MT levels are elevated beyond this optimal range by toxicant exposure, we predict that significant declines in immune function will occur. We plan to evaluate these hypotheses by using two recently derived mouse strains that are both congenic with C57BL/6J. The transgenic MT strain has multiple Mt1 genes that drive MT overexpression, and the second carries targeted disruptions of the Mt1 and Mt2 genes. Our specific aims are:(1) to test the hypothesis that manipulations of metallothionein gene dose will alter the immunosuppressive consequences of exposure to cadmium, (2) to test the hypothesis that metallothionein overproduction will decrease the available oxidant in leukocytes and diminish oxidant-related damage to leukocyte plasma membranes in cells harvested from animals exposed to immunosuppressive doses of cadmium, (3) to test the hypothesis that toxicant-induced metallothionein will alter the sub-cellular distribution and tissue distribution of essential and toxic metals to immune organs and cells in the cadmium-exposed animal, and (4) to test the hypothesis that metallothionein gene dose in an animal will influence the signal transduction cascade and specific transcription factor activities in cadmium-exposed animals. This research will broaden our understanding of the pathogenic mechanisms by which environmental agents act to elicit disease, should contribute to our understanding of individuals that are especially sensitive to toxicant immunomodulation, and may suggest new avenues of therapeutic benefit in Cd and other toxicant-exposed patients.

描述（由申请人提供）：重金属阳离子（例如镉）广泛存在于环境中，可以作为有效的免疫抑制剂。 对许多免疫抑制毒物的生物反应之一是应激反应蛋白的产生。 金属硫蛋白 (MT) 是这组蛋白质的一个有趣的例子，在细胞稳态中发挥着几个关键作用。 MT 充当必需金属的储存库、有效的抗氧化剂、可以隔离有毒重金属的蛋白质以及多种转录因子的调节剂。 这些功能表明 MT 参与金属介导的免疫调节。 我们已经证明 MT 可以显着影响体内和体外的免疫功能。 该提议的基本前提是功能性免疫反应存在于最佳 MT 水平的背景下。 当 MT 水平因接触毒物而升高超出最佳范围时，我们预测免疫功能将发生显着下降。 我们计划使用两种最近衍生的小鼠品系来评估这些假设，这两种小鼠品系均与 C57BL/6J 是同源的。 转基因 MT 菌株具有多个驱动 MT 过度表达的 Mt1 基因，而第二个基因则对 Mt1 和 Mt2 基因进行有针对性的破坏。 我们的具体目标是：(1) 检验金属硫蛋白基因剂量的控制会改变镉暴露的免疫抑制后果的假设，(2) 检验金属硫蛋白过量产生会减少白细胞中可用氧化剂并减少与氧化剂相关的假设。从暴露于免疫抑制剂量镉的动物中采集的细胞中白细胞质膜受损，(3) 检验毒物诱导的假设金属硫蛋白将改变镉暴露动物中免疫器官和细胞的必需金属和有毒金属的亚细胞分布和组织分布，以及（4）检验动物中金属硫蛋白基因剂量会影响信号转导级联和镉暴露动物中的特定转录因子活性。 这项研究将拓宽我们对环境因素诱发疾病的致病机制的理解，有助于我们了解对毒物免疫调节特别敏感的个体，并可能为镉和其他毒物暴露患者的治疗益处提出新的途径。