A mechanism of metal-mediated immunosuppression

描述(申请人提供)：重金属阳离子，如镉，广泛存在于环境中，可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产生应激反应蛋白。金属硫蛋白(MT)是这组蛋白质中的一个有趣的例子，在细胞内稳态中扮演着几个关键的角色。MT作为必需金属的储存库，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，以及作为几种转录因子的调节因子。这些功能表明MT参与了金属介导的免疫调节。我们已经证明MT在体内和体外都能显著影响免疫功能。这一建议的基本前提是，功能性免疫反应存在于最佳MT水平的背景下。当MT水平因毒物暴露而升高超过这一最佳范围时，我们预测免疫功能将显著下降。我们计划通过使用两个最近衍生的小鼠品系来评估这些假设，这两个品系都是C57BL/6J的同源基因。转基因MT菌株有多个MT1基因驱动MT过度表达，第二个携带MT1和MT2基因的靶向干扰。我们的具体目标是：(1)检验操纵金属硫蛋白基因剂量将改变镉暴露的免疫抑制后果的假说；(2)检验金属硫蛋白过量产生将减少免疫抑制剂量镉暴露动物的细胞中可利用的氧化剂并减少与氧化剂相关的白细胞膜损伤的假说；(3)检验毒物诱导的金属硫蛋白将改变镉暴露动物免疫器官和细胞中必需金属和有毒金属的亚细胞分布和组织分布的假说。(4)验证动物体内金属硫蛋白基因剂量影响镉暴露动物信号转导级联和特异性转录因子活性的假说。这项研究将拓宽我们对环境因素引发疾病的致病机制的理解，有助于我们理解对毒物免疫调节特别敏感的个体，并可能为CD和其他毒物暴露患者提供治疗益处的新途径。

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.