It is proposed to investigate the effects of metals (Cu, Hg, Pb, Ni and Zn) on the structure and functions of murine and human lymphocytes with emphasis on Pb effects. This objective will be accomplished through experiments designed to determine the mechanisms by which physiologic and pharmacologic doses of metals alter lymphocyte proliferation, immunoglobulin synthesis, and T- cell helper and suppressor activities, as well as the interactions between the lymphocyte subsets and their factors such as IL2, gamma-IFN, TRF(Helper factors) and SF( Suppressor factors). In vivo (chronic) and in vitro (acute) exposures to the metals will be compared to investigate the mechanisms involved in the posited metal-induced modulation of the development and differentiation of immunocompetent cells in vivo. Since the thiol chemistry of murine and human lymphocytes is known to differ, in vitro metal effects on murine and human lymphocytes will be compared for differences and assessment of the involvement of cellular thiols. Analysis of metal alteration of endogenous lymphocyte surface proteins will aid in evaluating how metals influence the characteristics of the lymphocyte subsets. Analysis of metal-induced alteration of the antigenicity of cell surface self-constituents will aid in assessing the potential development of autoimmune problems. In addition to quantitation of cell surface modifications influenced by the metals, intracellular parameters will be examined, including mRNA and protein expression of specific immune associated molecules, Ca flux, and glutathione/metallothionein quantitation and assessment of their cellular redistributions. Macrophage development, antigen handling, factor production and growth will be emphasized. Evaluation of metal induced modulation of lymphocyte physiology and of the immunoregulatory pathways will aid in the analysis of metal toxicity. An immunological, biochemical, and molecular and cellular biological approach to evaluation of these metals will help in identifying the health hazard to certain populations and individuals.
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