A mechanism of metal-mediated immunosuppression

金属介导的免疫抑制机制

• 批准号: 6679311
• 负责人: MICHAEL A LYNES
• 金额: $ 31.42万
• 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/6679311
• 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）在环境中被广泛发现，并且可以充当有效的免疫抑制剂。 对许多免疫抑制有毒物质的生物学反应之一是产生压力反应蛋白。 金属硫蛋白（MT）是这组蛋白质的一个有趣的例子，并且在细胞稳态中起了一些关键作用。 MT充当必需金属的储层，作为一种有效的抗氧化剂，作为一种可以隔离有毒重金属的蛋白质，并作为几种转录因子的调节剂。 这些功能暗示MT在金属介导的免疫调节中。 我们已经表明，MT可以显着影响体内和体外的免疫功能。 该提案的基本前提是在最佳水平的MT水平的背景下存在功能性免疫反应。 当MT水平通过有毒物质暴露升高到最佳范围之外时，我们预计免疫功能会显着下降。 我们计划通过使用两种均与C57BL/6J的近来衍生的小鼠菌株来评估这些假设。 转基因MT菌株具有多个MT1基因，可驱动MT过表达，第二个带有MT1和MT2基因的靶向破坏。 我们的具体目的是：（1）检验以下假设：金属硫硫代基因剂量的操纵将改变暴露于镉的免疫抑制后果，（2）测试金属丝蛋白过量产生的假设，即产生了金属蛋白的过度生产将减少白细胞中的氧化损伤，从而减少氧化量的氧化损伤，从而降低了氧化量的危害量，并降低了氧化量的肿瘤量。 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暴露于镉的动物。 这项研究将扩大我们对环境药物作用引起疾病的致病机制的理解，这应该有助于我们对对毒物免疫调节特别敏感的个体的理解，并可能暗示在CD和其他有毒物质暴露的患者中对治疗性益处的新途径。