The long-term objective of this research is to determine the mechanisms and the consequences of Pb modulation of cell-mediated and humoral immunity. This project proposes to advance an understanding of the mechanisms whereby Pb exhibits diverse effects on the activation, elaboration of cytokines, immune effector functions, and regulation of infectious disease pathogenesis of Th1 and Th2 cells. The hypothesis to be tested is that the diverse effects of Pb on the immune response are mediated by its differential effects on the expression and immune effector functions of Th1 and Th2 specific cytokines. An in vitro culture system will be employed to develop a systematic, quantitative analysis of the effects of Pb on the Th1/Th2 dichotomy, which will link effects of Pb on signal transduction components to the production of distinct cytokines and subsequently to immune effector functions. Lastly, the in vitro findings will be extrapolated and tested in Pb-intoxicated mice in vivo. Specifically, the proposal is designed to comprehensively and systematically compare and contrast the effects of Pb on i) the production of the Th1 and Th2 respective autocrine growth factors, mainly IL-1 and IL-4; ii) biochemical signal transduction components that may differentiate the Th subsets including phospholipase C, protein kinase C, vitamin-D3 receptor expression and vitamin-D3 responsiveness; iii) the production of Th1 and Th2 effector cytokines including IFN-gamma, IL-5, IL-6, IL-10; iv) Th1- and Th2-mediated B cell differentiation, Ig class switching, and Mo activation; v) host resistance to a pathogen, Leishmania, for which disease resolution vs progression is controlled by Th1 vs Th2 activities in vivo. In summary, this research will advance an understanding of mechanisms and consequences of immunomodulation by an important environmental toxicant. Characterizing the mechanisms by which Pb exposure (e.g., children) or Pb accumulation (e.g., aging), and may contribute to an understanding of the pathogenesis and etiology of immune deficiencies and autoimmune diseases. Finally the concepts developed may provide knowledge of immune function, in general, as well as insight on the action of Pb in other cells and tissues.
