The long-term goal of this project is to characterize the effects of a moderate period of suboptimal zinc on host defense systems and identify the underlying mechanisms causing the defects, using the mouse as a model system. Mononuclear phagocytes (MNP) from ZD mice were unable to take up or kill parasites unless preincubated with zinc. Experiments are proposed to examine the status of early reactions of the oxygen burst thought to be Zn-dependent as well as antigen processing and production of interleukin I, all of which are essential to host defense and may be defective. The density and distribution of cell surface proteins (FcR, CRIII, Iak, F4/80) that preliminary data indicate may also be altered in MNP from ZD mice will be quantitated to provide a more complete picture of the status of these cells. Conversely, lymphocytes from ZD mice showed no evidence of defects in function. Thus the reduced capacity of ZD mice to mount antibody and cell mediated responses appears to be related to the reduction in total numbers of lymphocytes observed throughout the peripheral immune system of the AZ mouse (lymphopenia). Therefore, failure of the bone marrow (BM) to produce adequate numbers of lymphocytes may represent the seminal event that causes the rapid demise of the immune system in ZD. Experiments are proposed to verify preliminary observations that ZD causes significant reductions in the total numbers of nucleated stem cells as well as Initially, proliferation and cycling of precursor cells in the bone marrow may be altered since Zn is critical to these processes. As Zn deficiency progresses, corticosterone (CS) is produced which is known to cause programmed death of immature thymocytes and may cause apoptosis of the immature, precursor lymphoid cells of the BM as well. Experiments are proposed to determine the role (s) of suboptimal Zn and CS in the suppression of lymphopoiesis associated with ZD in order to identify the underlying mechanisms causing lymphopenia.
