Previous studies by the applicant have shown that in the absence of hypozincemia there may be adverse immunological effects when the deficiency of zinc is only mild or marginal. In these cases, the diagnosis of zinc deficiency was based on decreased levels of zinc in lymphocytes, granulocytes, and platelets. Inasmuch as the mRNA of metallothionein-2 (liver MT) is under the regulatory control of zinc, the assay of MT-2 and zinc in the plasma may provide a simple and accurate assessment of zinc status. The applicant has produced a monoclonal antibody to MT-2 from human liver and has succeeded in setting up a radio-immune assay for MT-2 in human plasma. With this technique, it will be possible to assess zinc status in experimental human model subjects, in whom a mild deficiency of zinc will be induced by dietary means and correlate plasma MT-2 levels with cellular zinc, and lymphocyte ecto 5' nucleotidase activity during baseline, zinc restricted, and zinc repleted phases. Additionally with the use of 70Zn, mobilizable body zinc pool measurement will be used to further define the status of zinc in the experimental human model subjects during baseline, zinc restricted, and zinc repleted phases. If these studies show that measurement of MT-2 and zinc in plasma truly reflected zinc status in humans, the diagnostic procedures can be simplified to develop a commercial radio-immune assay kit for MT-2 assay. Zinc plays an important role in immune functions in both man and experimental animals. Inasmuch as a marginal deficiency of zinc may be prevalent throughout the world, the proposed studies will provide techniques for assessing zinc status and relate this to various immunological dysfunctions commonly observed in cases of human zinc deficiency and provide mechanisms of zinc action on cell mediated immune functions. Previous studies in experimental human model subjects have shown that active thymulin peptide in serum and IL-2 production by mononuclear cells are affected early, whereas impairment of IL-1 production and NK cell activity appears later during the zinc restricted period. The applicant has also observed decreased lymphocyte ecto 5' nucleotidase activity (believed to be an enzymatic marker of cell maturity) early during the zinc restricted phase. The applicant proposes to investigate three mechanisms by which mild zinc deficiency could cause impaired IL-1 production, IL-2 production and NK cell activity: 1) reductions in the proportions of the relevant cells, 2) suppression of the functional activity of the relevant cells by prostaglandins and/or TGFB, and 3) intrinsic defects in the functional activities of the relevant cells.
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