MECHANISM OF METAL MEDIATED IMMUNOSUPPRESSION

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DESCRIPTION: (Adapted from the Investigator's Abstract) Heavy metals (such as Cd, Hg, Ni, Zn, Cu, and Pb) are increasingly important contaminants of air, water, and soils. One of the critical biological systems which can be altered by exposure to heavy metals is the immune system, where inappropriate changes in immune capacity can result in immunodeficiency or autoimmune disease. While there is a great deal of interest in the mechanisms by which heavy metals alter immunity, there remain many unresolved issues. In preliminary studies, the investigators have examined the contributions that MT (a small, cysteine-rich metalloprotein that is rapidly induced in cells following heavy metal exposure) might make to altered immune activity. Metallothionein may be responsible for some of the forms of humoral immunosuppression associated with metal exposure. For example, the investigators have found that MT suppresses specific T-dependent humoral responses, and that some aspects of macrophage function are altered by MT. They have also found that monoclonal antibodies to MT developed in our laboratory can block some in vivo immunomodulatory activities of MT. The investigator's findings suggest that MT induced by heavy metal exposure (or indeed by exposure to other toxicants) is responsible for decreases in immunity as a consequence of antigen-presenting cell/helper T-cell interactions. The central parameters of the humoral response that are potential targets of the suppressive effect of MT will be evaluated. These experiments will establish the mechanisms by which suppressive effects occur. The Specific Aims are to: (1) explore the dynamics of in vivo MT interactions with the immune system and to determine if suppression of humoral immunity is found in both T-dependent and -independent responses, (2) to examine the effects of MT on the role that T-lymphocytes play in regulation of the humoral immune response, (3) to determine whether the interactions of helper T-cells and macrophages are altered by MT, and (4) to establish whether patterns of B-cell differentiation are altered by the presence of MT. This research will have important implications both for the identification of individuals at particular risk for immune disease as a consequence of heavy metal exposure, and for the diagnosis and treatment of individuals exposed to excessive levels of these important environmental toxins.