Xenobiotics can exert their immunotoxic effects via direct and/or indirect mechanisms. One possible mechanism by which a xenobiotic can exert an indirect effect on the immune response is by inducing a neurotoxic effect in vivo which indirectly influences homeostatic immune function. It is the overall goal of this research project to understand the role neurotransmitters play in regulating normal immune function and how these functions can be altered indirectly by an environmental insult to the nervous system. Our first specific aim is to determine the cellular mechanism responsible for both the beta-2 adrenoceptorinduced enhancement and the alpha-2 adrenoceptor-Induced suppression of the antIbody response. Using a limiting dilution system to culture antigen-specific T and B lymphocytes, we show that beta-2 adrenoceptor stimulation induces an enhanced antibody response by increasing the number of B cells which differentiate in response to a soluble T cell-dependent antigen, without affecting the number of B cells produced by an individual precursor clone. Our second specific aim is to establish an in vivo model that mimics the in vitro model as closely as possible. The animal model utilizes the scid (severe combined immune-deficient) mouse. These mice serve as hosts for adoptively transferred murine antigen-specific T cells and B cells. Using this model system, we will study the role sympathetic nervous system function plays in maintaining normal Immune function after an environmental Insult. Preliminary results show that reconstitution of scid mice with increasing numbers of antigen-specific T and 8 cells produces a mouse capable of secreting antigen-specific antibody after a primary immunization with a specific antigen. An understanding of both direct and indirect mechanisms of immunotoxicity will allow for (1) a more definitive characterization of the seemingly contradictory immunomodulatory results produced by xenobiotics in vitro as opposed to in vivo, and (2) the design of pharmacologic interventions capable of modulating the intensity of the xenobiotic-induced effect.
