SUPPRESSION OF HUMORAL IMMUNITY BY BENZENE METABOLITES

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The long-term objectives of this study center upon understanding the mechanisms by which exposure to low levels of benzene via the water supply of individuals residing close to industries using benzene as a solvent mediates the suppression of humoral immune responses. Although exposure to high levels of benzene in the workplace can result in the development of hematopoietic dyscrasias and certain forms of tumors, this study will focus upon possible immunosuppressive capabilities of the metabolic products of benzene metabolism in the liver following exposure to low levels of benzene over an extended period of time. The first part of the proposal deals with defining the levels at which these compounds impact with the humoral immune system. For this purpose, normal, resting, murine B cells will be exposed in vitro to varying concentrations of benzene metabolites, either singly or in combinations of metabolites, while being induced to proliferate and differentiate. In some experiments, the cells will be activated polyclonally by phorbol ester and ionomycin, by lipopolysaccharide, by anti-immunoglobulin plus lymphokines, or by anti-CD3 treated, fixed T helper (TH) cells plus lymphokines. The cells will be evaluated for levels of RNA and DNA synthesis, percent cells entering the various stages of the cell cycle, number of viable cells present at each time point, and for the transduction of a number of biochemical signals. In addition, populations of antigen-specific B cells exposed to benzene metabolites will be challenged in vitro with specific antigen (both thymus-independent and thymus-dependent) and when appropriate, irradiated, carrier-specific Th cells. The effect of the metabolites upon induction of antibody synthesis by polyclonal stimulants and specific antigen will be assessed. Finally, lymphokine-mediated class switching will be studied. These experiments will define the levels at which the benzene metabolites interfere with the developing humoral response. In the second part of the proposal, mice will be exposed to benzene in their drinking water for up to 12 months. At various times, animals will be sacrificed and B cells recovered from both the spleen and mesenteric lymph nodes for in vitro evaluation of function as described above. These experiments will determine if different secondary lymphoid compartments are more susceptible to the benzene metabolites released from the liver. In addition, cells exposed for much longer periods of time to the metabolites can be studies in similar ways as cells exposed short-term vitro.