A mechanism of metal-mediated immunosuppression

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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.