This proposal represents a multidisciplinary approach to the study of interactions between the mammalian nervous system and the immune system, which may be central to the impact of psychosocial and behavioral factors on susceptibility to disease. The proposed research is directed specifically to the noradrenergic portion of the sympathetic nervous system, which, via its innervation of lymphoid organs, may exert a significant modulatory influence on immune responsiveness. A pharmacologic approach will be employed to deplete or enhance neurally-derived norepinephrine (NE) in the periphery, or to block its binding to beta adrenergic receptors on lymphocytes. This will be achieved by adult or neonatal sympathetic denervation with the neurotoxic drug 6-hydroxydopamine to deplete virtually all peripheral neural NE, or by blocking neuronal reuptake of NE with protriptyline, to prolong the presence and availability of NE in the tissues. Changes in catecholamine levels will be confirmed by neurochemical analysis. Alternatively, the beta blocking agent propranolol will be given in chronic form to prevent the interaction of released NE with its receptors on lymphocytes. The consequences of these treatments will be evaluated at several levels. First, antibody and cell-mediated immune responses to specific antigens in vivo will be measured. Spleens and lymph nodes will be examined, not only to document the neural alterations anatomically, but also to determine changes in the structural relationships among lymphocyte subclasses, macrophages, dendritic cells and mast cells. The traffic patterns of circulating lymphocytes will be studied, assessing the dynamics and positioning of migrating cells in """"""""resting"""""""" or """"""""activated"""""""" lymphoid organs. Similarly, the localization and retention of radiolabelled antigens in immune and nonimmune mice will be followed. Finally, lymphocyte behavior will be examined at the cellular level, by analyzing beta adrenergic receptors, receptor-mediated induction of cyclic AMP production, and proliferative responses of T and B cells in vitro to mitogenic stimuli. Information derived from these studies of neural-immune interactions will form an essential foundation for a better understanding of the link between the brain, behavior, and the development and resolution of a wide range of diseases.
