A mechanism of metal-mediated immunosuppression

描述（由申请人提供）：重金属阳离子（如镉）广泛存在于环境中，可作为强效免疫抑制剂。 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，在细胞内稳态中起着几个关键作用。 MT作为必需金属的储存库，作为有效的抗氧化剂，作为可以螯合有毒重金属的蛋白质，以及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。 我们已经证明MT可以在体内和体外显著影响免疫功能。 该建议的基本前提是，在MT的最佳水平的背景下存在功能性免疫应答。 当MT水平升高超过这个最佳范围的毒物暴露，我们预测，免疫功能将发生显着下降。 我们计划使用两个最近衍生的小鼠品系，都是同源的C57 BL/6 J来评估这些假设。 转基因MT菌株具有驱动MT过表达的多个Mt 1基因，第二个携带Mt 1和Mt 2基因的靶向破坏。 我们的具体目标是：（1）检验金属硫蛋白基因剂量的操作将改变暴露于镉的免疫抑制后果的假设，（2）检验金属硫蛋白过量产生将减少白细胞中可用的氧化剂并减少对从暴露于免疫抑制剂量的镉的动物收集的细胞中的白细胞质膜的氧化剂相关损伤的假设，（3）检验毒物诱导的金属硫蛋白将改变必需和有毒金属对暴露于镉的动物的免疫器官和细胞的亚细胞分布和组织分布的假设，（4）验证金属硫蛋白基因剂量对镉暴露动物体内信号转导级联反应和特异性转录因子活性的影响。 这项研究将扩大我们的理解的致病机制，环境代理人的行为，引发疾病，应有助于我们的理解的个人，特别是对有毒的免疫调节敏感，并可能提出新的途径，镉和其他有毒物质暴露的患者的治疗效益。

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.