Our goal for this 5-year proposal is to further characterize the effects of exposure to 2,3,7,8-TCDD on B-cell differentiation. These studies are base don the following observations generated by our laboratory: (1) TCDD suppresses the AB response to a number of stimuli, as assessed both when TCDD and the stimulus are administered to cells from naive mice in culture, and when cells from TCDD-treated mice are immunized in culture; (2) The B- cell represents the primary target for TCDD; (3) TCDD stimulates the phosphorylation of a number of endogenous proteins in B-cells, but not T- cells; at least one protein (ie., 45 KDa) is not phosphorylated by PMA, a comparative control; (4) TCDD stimulates background kinase activity in B- cells, but not T-cells, which is not due to an activation of PKC; and (5) TCDD enhances the background AB response in the absence of any other stimulus. The primary objectives of this investigation are twofold. First, we will characterize the effects of TCDD on a defined model of B- cell maturation, in which specific factors are sequentially added to move isolated B-cells through the various stages of the cell cycle and ultimately to an AB-secreting cell. We will be particularly interested in the effects of TCDD alone on the activation and differentiation of B-cells, and will primarily address two possible mechanisms: (i) TCDD produces a profile of activity which is similar to IL4;p and (ii) TCDD causes the aberrant expression of receptors for various growth or differentiation factors. The second objective will be to further characterize the nature of the kinase system which is acrivated by TCDD and the proteins which are subsequently phosphorylated. We will specifically address whether these biochemical events are causally related to the functional defects. Our initial focus will be on the possible role by a tyrosine kinase. We believe that these studies are significant both because they will provide specific information about the site and mechanism of action of TCDD on B- cell maturation, and because they may provide a more general model for the toxic effects of TCDD on a number of other cell systems, which have been characterized by a change in the maturational state.
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