Immunologists have long believed the regulation of the immune system to be autonomous, that the participating cells were limited to those cells recognized as members of the immune system.The belief that immune regulation occurs in the absence of any modulatory influence from the central nervous system CNS is (or was until very recently) accepted by all but a tiny minority in the field of immunology. However,there are numerous reports in the literature which have demonstrated that various immune responses may be altered by hormones, including the sympathetic neurotransmitter norepinephrine (NE) in vitro, provided that the large doses needed to activate the lymphocyte beta-adrenergic receptor are used. Also, recent neuroanatomical evidence has shown the extremely intimate nature of the connections which exist between the sympathetic nervous system (SNS) splenic lymphocytes. Experimental evidence is increasing to indicate that these connections are functional in the sense that by altering them immune responsiveness is also altered. This application will propose a series of studies which will increase our understanding potential regulatory links between the SNS and the immune system in the murine spleen. The hypothesis is; The i SNS is activated during an immune response. The (NE) released in the spleen as a result of this activation modulates the plaque forming cell (PFC) response to the T-dependent antigen sheep red blood cells (SRBC). Because of the role played by the SNS during a normal immune response pharmacologic inter- ventions which disrupt the sympathetic innervation of the spleen result in an altered antibody response to antigens. To evaluate the validity of this hypothesis the following specific aims are proposed- 1) Determine how the state of activation of T and B lymphocytes affects the characteristics (density and affinity) of their B-adrenergic receptors. 2) Establish that the effect of peripherally administered 6-hydroxydopamine (6-OHDA) on the in vivo and in vitro murine humoral immune response is not attributable to a cytotoxic effect on lymphocytes or accessory cells. 3) Determine which cell type(s) are affected by the reduced catecholamine content of the spleen and how they may be responsible for the reduced humoral immune response in chemically sympathectomized mice. 4) Establish the kinetics of the turnover rate of NE in the murine spleen during a humoral immune response. 5) Determine if the activation of 8-adrenergic receptors on murine B-cells is able to increase the rate of differentiation of these cells. To accomplish these aims a combination of in vitro and in vivo studies are planned. Experiments have been designed both to test the nature and kinetics of SNS signals to the spleen during an ongoing immune response, as well as to evaluate the effect of these signals on lymphocyte function. In addition, studies are planned to critically analyze the effects of 6-OHDA, which has been used as a major pharmacologic tool to link the SNS and immune system in past studies. Completion of the experiments proposed should contribute to an understanding of the nature and the extent, of SNS regulation of the antibody response in the spleen.
