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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37MH042076-09
Application #
2245335
Study Section
Special Emphasis Panel (NSS)
Project Start
1986-05-01
Project End
1999-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Rochester
Department
Biology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Thyagarajan, Srinivasan; Madden, Kelley S; Boehm, Gary W et al. (2013) L-Deprenyl reverses age-associated decline in splenic norepinephrine, interleukin-2 and interferon-? production in old female F344 rats. Neuroimmunomodulation 20:72-8
ThyagaRajan, Srinivasan; Madden, Kelley S; Teruya, Brian et al. (2011) Age-associated alterations in sympathetic noradrenergic innervation of primary and secondary lymphoid organs in female Fischer 344 rats. J Neuroimmunol 233:54-64
Kelley, Sheila P; Moynihan, Jan A; Stevens, Suzanne Y et al. (2003) Sympathetic nerve destruction in spleen in murine AIDS. Brain Behav Immun 17:94-109
Rice, P A; Boehm, G W; Moynihan, J A et al. (2002) Chemical sympathectomy alters numbers of splenic and peritoneal leukocytes. Brain Behav Immun 16:62-73
ThyagaRajan, Srinivasan; Felten, David L (2002) Modulation of neuroendocrine--immune signaling by L-deprenyl and L-desmethyldeprenyl in aging and mammary cancer. Mech Ageing Dev 123:1065-79
Kelley, Sheila P; Moynihan, Jan A; Stevens, Suzanne Y et al. (2002) Chemical sympathectomy has no effect on the severity of murine AIDS: murine AIDS alone depletes norepinephrine levels in infected spleen. Brain Behav Immun 16:118-39
Rice, P A; Boehm, G W; Moynihan, J A et al. (2002) Chemical sympathectomy increases numbers of inflammatory cells in the peritoneum early in murine listeriosis. Brain Behav Immun 16:654-62
Madden, K S; Felten, D L (2001) Beta-adrenoceptor blockade alters thymocyte differentiation in aged mice. Cell Mol Biol (Noisy-le-grand) 47:189-96
Bellinger, D L; Felten, D L; Lorton, D et al. (2001) Effects of interleukin-2 on the expression of corticotropin-releasing hormone in nerves and lymphoid cells in secondary lymphoid organs from the Fischer 344 rat. J Neuroimmunol 119:37-50
Rice, P A; Boehm, G W; Moynihan, J A et al. (2001) Chemical sympathectomy increases the innate immune response and decreases the specific immune response in the spleen to infection with Listeria monocytogenes. J Neuroimmunol 114:19-27

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