The overall objective of the research proposed is to evaluate the effects of epoxidized toxicants, both naturally occurring and man- made, on the murine immune system. A large number of these epoxidized compounds are toxic, and as humans are exposed to these compounds either from industrial or environmental sources, epoxides pose significant hazards to human health. The specific objectives of the proposal are: 1) Evaluate the immunosuppressive (or immunopotentiative) effects of selected epoxides; 2) Characterize the mechanism(s) of immunosuppression; and 3) Attempt to modify these immunosuppressive effects. These epoxidized compounds will be examined for their effects on the immune system at sublethal doses. Three experimental protocols will be used. The first will involve a totally in vivo system with epoxide treatment, immunization and analysis of immune function performed in vivo; the second a combination of in vivo treatment with epoxides and in vitro evaluation of immune function, while the third protocol will be totally in vitro. In addition to pathology, both cell and humoral-mediated immunity will be monitored. Among the parameters of immune function determined will be the effects on host resistance, delayed hypersensitivity, mitogen and cytotoxic T-lymphocyte response, Natural Cell Mediated Cytotoxicity (both NK and NC), antibody response to antigen challenge, macrophage function and lymphokine production. Standard immunologic assays will be utilized to asses these functions. The effects of epoxides on cell populations will also be assessed with the aid of specific antibodies and a fluorescence activated cell sorter. We will also determine the effect of epoxide treatment on lipid peroxidation and glutathione levels, and evaluate how this affects immune response. In addition, the capability of lymphocytes to metabolize epoxides will also be determined. Finally we will attempt to characterize the mechanisms by which epoxides exert their immunosuppressive effects. In particular, the ability of epoxides to interfere with target recognition and binding and its subsequent killing of target cell will be determined by single cell binding assays, for both cytotoxic T-lymphocyte response and natural killer activity. Macrophage function will be determined by IL1 production, phagocytosis and antigen presentation.
| Tomar, R S; Lim, S; Gill, S S (1991) The effects of epoxidized xenobiotics on mitogen responsiveness and antibody-producing ability of murine spleen cells in vitro. Int J Immunopharmacol 13:57-65 |
| Chang, C; Gill, S S (1991) Purification and characterization of an epoxide hydrolase from the peroxisomal fraction of mouse liver. Arch Biochem Biophys 285:276-84 |
