A mechanism of metal-mediated immunosuppression

描述（由申请人提供）：镉等重金属阳离子广泛存在于环境中，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）是这组蛋白中一个有趣的例子，在细胞稳态中起着几个关键作用。MT是必需金属的储存库，是一种有效的抗氧化剂，是一种可以隔离有毒重金属的蛋白质，也是几种转录因子的调节剂。这些功能暗示MT参与了金属介导的免疫调节。我们已经证明MT可以显著影响体内和体外的免疫功能。该建议的基本前提是，在最佳MT水平的背景下存在功能性免疫反应。当MT水平因毒物暴露而超过最佳范围时，我们预测免疫功能将出现显着下降。我们计划用两个新近获得的具有C57BL/6J基因的小鼠品系来评估这些假设。转基因MT菌株具有多个驱动MT过表达的Mt1基因，第二个携带靶向破坏Mt1和Mt2基因。我们的具体目标是：(1)验证金属硫蛋白基因剂量的操纵将改变镉暴露的免疫抑制后果的假设；(2)验证金属硫蛋白过量生产将减少白细胞中可用的氧化剂，并减少免疫抑制剂量镉暴露的动物细胞中白细胞质膜的氧化相关损伤的假设。(3)验证毒物诱导的金属硫蛋白会改变镉暴露动物免疫器官和细胞中必需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会影响镉暴露动物的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，有助于我们了解对有毒免疫调节特别敏感的个体，并可能为Cd和其他有毒暴露患者的治疗提供新的途径。

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.