During the -past 2 years of support for this project, we have shown that noradrenergic (NE) sympathetic nerve fibers abundantly innervate the parenchyma of the spleen and lymph nodes (LNs), and at some sites contact lymphocytes directly. NE fulfills the criteria for neurotransmission in the spleen, with cells of the immune system as targets, and shows many such characteristics in LNs. Denervation of spleen and LNs results in striking alterations in immune responses, with virtual abrogation of primary immune responses in popliteal LNs. We will test the general hypothesis that NE nerve terminals full the criteria for neurotransmission in adult mouse inguinal and popliteal LNs, with immune cells as targets, in Specific Aim 1, using: (1) double-label light immunocytochemistry for tyrosine hydroxylase (TH) in nerves and specific markers for lymphocyte subsets and macrophages; (2) with EM immunocytochemistry for TH+ nerve terminals abutting immune cells; (3) with neurochemical analysis of NE and its metabolites; and (4) with beta-adrenoceptor analysis on lymphocyte subsets and macrophages. We will test the general hypothesis that neural NE regulates immune responses through its influence on cell proliferation, compartmentation and distribution, and traffic in Specific Aim 2. We will denervate adult inguinal and popliteal LNs with surgical ganglionectomy or chemical sympathectomy, and will examine the effects on primary immune responses to KLH antigen. We will further explore mechanisms for such alterations with: (1) cell sorting of lymphocyte subsets and macrophages; (2) immunocytochemical analysis of lymphoid compartments of these LNs; (3) analysis of B and T lymphocyte proliferation; and (4) studies of lymphocyte traffic following denervation, with or without lymphocyte incubation in isoproterenol to down-regulate beta- adrenoceptors. These studies have relevance for 4 general areas of understanding: (1) nerve-target interactions in lymphoid organs that may determine immune competence and functional integrity; (2) neural channels by which psychosocial and environmental influences may exert their modulatory effects on immune function; (3) situations where altered immune responsiveness is proceeded by loss of innervation, such as generic autoimmune disorders and aging; and (4) AIDS, where lymphs compartmentation and organization in LNs breaks down, and neural-immune and interactions appear to be disrupted.
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