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K S Madden

Publications and source records attributed to K S Madden.

At least 19 recordsLinked to original sources
PubMed2001

One-trial conditioning of the antibody response to hen egg lysozyme in rats.

In Wistar rats, reexposure to a novel conditioned stimulus (CS) previously paired with a protein antigen, hen egg lysozyme (HEL) on a single conditioning trial increased anti-HEL IgG levels relative to conditioned rats that were not reexposed to the CS, conditioned rats that were preexposed to the CS, and nonconditioned rats. These results confirm previous findings that a single exposure to a CS associated with immunization is sufficient to elicit an antibody response upon subsequent reexposure to the CS in the absence of exogenous antigen.

Animals↗
PubMed2001

Beta-adrenoceptor blockade alters thymocyte differentiation in aged mice.

The thymus is the primary site for generation of naive T-lymphocytes in the young animal. With age, the thymus progressively involutes and fewer mature T-cells are produced and migrate to the periphery. With thymic involution, increased density of sympathetic noradrenergic (NA) innervation and concentration of norepinephrine (NE) have been observed. To determine if the age-related changes in thymocyte differentiation are modified by NE signaling through beta-adrenergic receptors, 2-month (mo) and 18-mo old BALB/c mice were implanted subcutaneously with pellets containing the non-selective beta-adrenoceptor antagonist nadolol. Four and one-half weeks later, thymus and peripheral blood were collected to assess changes in thymocyte differentiation and naive T-cell output by flow cytometric analysis of T-cell subpopulations. In old mice, but not in young mice, thymocyte CD4/CD8 co-expression was altered by beta-adrenoceptor blockade. In nadolol-treated old mice, the frequency of the immature CD4-8- population was increased, and the intermediate CD4+8+ population was reduced. A corresponding increase in the frequency of mature CD4-8+, but not CD4+8- cells was observed. The increase in CD4-8+ cells is most likely not mediated by more CD4-8+ cells undergoing positive selection, because CD3hi expression in the CD4+8+ population was not altered by nadolol. The percentage of CD8+44low naive cells in peripheral blood increased in nadolol-treated mice, suggesting that more CD4-8+ cells were exported from the thymus to the periphery. These results indicate that the age-associated increase in sympathetic NA innervation of the thymus modulates thymocyte maturation. Pharmacological manipulation of NA innervation may provide a novel means of increasing naive T-cell output and improving T-cell reactivity to novel antigens with age.

Adrenergic beta-Antagonists↗
PubMed2000

Anti-tumor effect of L-deprenyl is associated with enhanced central and peripheral neurotransmission and immune reactivity in rats with carcinogen-induced mammary tumors.

L-Deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, has previously been shown to improve immune responses and restore noradrenergic (NA) nerve fibers in the spleen of old rats. In tumor-bearing rats, L-deprenyl inhibited tumor incidence and enhanced tuberoinfundibular dopaminergic (TIDA) neurotransmission in the hypothalamus. The aim of the present study was to investigate whether alterations in sympathetic NA activity and cellular immune responses in the spleen, and TIDA activity in the hypothalamus, accompany deprenyl-induced regression of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced mammary tumors. Rats with DMBA-induced mammary tumors were treated with 0, 2.5 mg, or 5.0 mg/kg body weight of deprenyl daily for 13 weeks. Saline-treated tumor-bearing rats exhibited reduced splenic IL-2 and IFN-gamma levels, and lowered splenic norepinephrine (NE) concentration and hypothalamic dopaminergic activity, compared to rats without tumors. In contrast, treatment with 2.5 mg/kg and 5.0 mg/kg of deprenyl reduced the number and size of mammary tumors. Deprenyl-induced tumor regression was accompanied by increased immune measures in the spleen, including enhanced IL-2 and IFN-gamma production, and NK cell activity. Neural measures enhanced by deprenyl included NE concentration in the spleen and TIDA neuronal activity in the hypothalamus. These results suggest that (1) mammary tumorigenesis is associated with the inhibition of sympathetic NA activity in the spleen, TIDA activity in the hypothalamus, and cell-mediated immunity, and (2) reversal of the inhibition of catecholaminergic neuronal activities of the central nervous system and peripheral nervous system by deprenyl may enhance anti-tumor immunity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Alterations in T lymphocyte activity following chemical sympathectomy in young and old Fischer 344 rats.

In aged Fischer 344 (F344) rats, sympathetic noradrenergic (NA) innervation of the spleen is markedly diminished compared with young rats. To determine if diminished NA innervation can still provide functional signals to splenic T cells, young (3 months old) and old (17 months old) F344 rats were treated with the NA-selective neurotoxin, 6-hydroxydopamine (6-OHDA) to destroy peripheral NA nerve fibers. In 3-month-old rats, no alterations in spleen cell Con A-induced T cell proliferation, IL-2 or IFN-gamma production were observed up to 15 days after sympathectomy, when splenic NE was maximally depleted. By 21 days post-sympathectomy, when NE levels had partially recovered, Con A-induced proliferation and IFN-gamma production, but not IL-2 production, were reduced in sympathectomized animals. After day 21 post-sympathectomy, no alterations in T cell functions were observed in sympathectomized animals. In 17-month-old rats, spleen cell Con A-induced proliferation and IL-2 production were reduced 5 days after sympathectomy in the absence of changes in CD5+ T cells or IFN-gamma production. Desipramine pretreatment, to block 6-OHDA uptake and prevent sympathectomy, completely blocked the 6-OHDA-induced effects, demonstrating that the destruction of NA nerve fibers is required. After day 5 post-sympathectomy, no sympathectomy-induced alterations in Con A-induced T cell functions were observed in old animals. These differences between young and old rats demonstrate that old animals are more susceptible to loss of sympathetic NA innervation, perhaps because compensatory mechanisms are limited. The sympathectomy-induced reduction in T cell proliferation indicates that splenic NA innervation in old animals, though diminished, can exert a positive regulatory influence on T lymphocyte function. Further study of sympathetic neural-immune interactions in the aged rat may provide a means to improve T cell responsiveness in aging.

Aging↗
PubMed2000

Restoration of splenic noradrenergic nerve fibers and immune reactivity in old F344 rats: a comparison between L-deprenyl and L-desmethyldeprenyl.

L-deprenyl, a monoamine oxidase-B inhibitor, partially reversed the age-associated decline in splenic sympathetic noradrenergic (NA) innervation and immune reactivity in old male rats. The purpose of the present study was to examine whether the effects of deprenyl on splenic sympathetic NA nerve fibers and immune functions are mediated through a metabolite of deprenyl, L-desmethyldeprenyl. Old male F344 rats were treated with 0, 0.25, or 1.0 mg L-(-)-deprenyl/kg BW; 0.025, 0.25, or 1.0 mg L-(-)-desmethyldeprenyl/kg BW; and 1.0 mg D-(+)-desmethyldeprenyl/kg BW i.p. daily for 8 weeks. The animals were sacrificed after a 10-day drug wash-out period and the spleens were removed for histofluorescence, immunocytochemistry, neurochemical, and immunological analysis. The volume density of NA nerve fibers was increased in the spleens of deprenyl- and L-desmethyldeprenyl-treated old rats. Con A-induced IFN-gamma production by spleen cells was elevated in 1.0 mg/kg deprenyl- and L-desmethyldeprenyl-treated rats in comparison to saline- and D-desmethyldeprenyl-treated old rats. Deprenyl and desmethyldeprenyl treatment did not alter the percentage of CD5+ T cells, but treatment with 1.0 mg/kg deprenyl and 0.025 mg/kg L-desmethyldeprenyl prevented the decline in the percentage of sIgM(+)B cells in the spleens of old rats. These results suggest that L-desmethyldeprenyl may be as equipotent as deprenyl in preventing age-associated diminution in splenic sympathetic NA innervation and immunocompetence.

Adrenergic Fibers↗
PubMed1999

Effects of L-deprenyl treatment on noradrenergic innervation and immune reactivity in lymphoid organs of young F344 rats.

Sympathetic noradrenergic (NA) neuronal activities in the thymus, spleen and mesenteric lymph nodes (MLN) and immune responses in the spleen were examined in young male F344 rats treated daily with 0, 0.25 mg, or 2.5 mg/kg body weight of L-deprenyl, an irreversible monoamine oxidase-B (MAO-B) inhibitor. Rats were treated daily for 1, 15, or 30 days, and sacrificed 7 days after the last deprenyl treatment. Deprenyl treatment increased norepinephrine (NE) content in the spleen without modifying the pattern and density of NA innervation in the splenic white pulp. The concentration of NE was unaltered in the thymus, but it was increased in the MLN of deprenyl-treated rats. One day of treatment with deprenyl decreased splenic NK cell activity while 15 days of deprenyl treatment enhanced splenic NK cell activity. Deprenyl elevated Con A-induced T lymphocyte proliferation following 30 days of treatment, but did not alter spleen cell Con A-induced IL-2 production or the percentage of CD5 + T cells in the spleen. A moderate decrease in the percentage of sIgM + B cells was observed in the spleens of 15- and 30-day deprenyl-treated rats. These results suggest that deprenyl has sympathomimetic action on sympathetic NA nerve fibers in the spleen; the enhancement of NA neuronal activity may contribute to the modulation of immune responses in the spleen.

Adrenergic Fibers↗
PubMed1998

L-deprenyl-induced increase in IL-2 and NK cell activity accompanies restoration of noradrenergic nerve fibers in the spleens of old F344 rats.

Previously, we have hypothesized a causal relationship between some measures of immunosenescence and the age-related decline in sympathetic noradrenergic (NA) nerve fibers in spleen and lymph nodes of F344 rats. In the present study, we investigated this interrelationship further by measuring NK cell activity, Con A-induced IL-2 production, norepinephrine (NE) concentration, and morphological localization of NA and neuropeptide-Y (NPY) nerve fibers in the spleens of old (21 months old) male F344 rats after 10 weeks of daily treatment with low doses of L-deprenyl, an irreversible monoamine oxidase-B inhibitor, followed by a 9-day wash-out period. NK cell activity and Con A-induced IL-2 production were increased in deprenyl-treated old rats in comparison to untreated and saline-treated old rats. Deprenyl treatment did not alter the percentage of CD5+ T-cells, but moderately increased the percentage of sIgM+ B-cells in the spleens of old rats. In addition to changes in immune responses, NE content and the volume density of NA and NPY nerve fibers were partially augmented in the spleens of deprenyl-treated old rats. In a separate study, various concentrations of deprenyl were added in vitro to spleen cells from young and old F344 rats to examine the direct effects of the drug on Con A-induced IL-2 production. In contrast to in vivo treatment, in vitro addition of deprenyl did not alter the Con A-induced IL-2 production by splenocytes from old rats. Together, these results suggest that the ability of deprenyl to enhance certain immune responses are interlinked to the restoration of sympathetic NA and NPY nerve fibers in the spleens of old rats.

Aging↗
PubMed1998

Alterations in sympathetic noradrenergic innervation in lymphoid organs with age.

Previous work in our laboratories has shown a selective age-related loss of sympathetic noradrenergic (NA) nerves from the spleen and lymph nodes of rats. In contrast, NA nerve fiber density is dramatically increased in the thymus of aged mice and rats. We hypothesize that the diminished splenic NA innervation in old rats is due to cumulative oxidative metabolic autodestruction of NA nerve terminals by high concentrations of norepinephrine released during specific time periods of immunologic reactivity. These old animals show a loss of NK cell activity, diminished T-cell proliferation, and diminished cell-mediated immunity. To assess the plasticity of NA nerve fibers in the aged rat spleen, male Fischer 344 rats at 24 months of age were treated for 2 months with daily injections of 0.25 or 1.0 mg/kg/day of L-deprenyl, followed by a 10-day drug washout period. The L-deprenyl-treated rats showed a remarkable sprouting of NA nerves into the splenic white pulp, with regrowth into appropriate vascular and parenchymal compartments. Rats with enhanced NA nerve regrowth showed increased IL-2 and IFN-gamma production and NK cell activity compared with vehicle injected or uninjected age-matched control rats. We proposed that L-deprenyl stimulates NA nerve regrowth into secondary lymphoid organs, which leads to partial recovery of measures of immunosenescence.

Aging↗
PubMed1998

Noise-induced spiral waves in astrocyte syncytia show evidence of self-organized criticality.

Long range (a few centimeters), long lived (many seconds), spiral chemical waves of calcium ions (Ca2+) are observed in cultured networks of glial cells for normal concentrations of the neurotransmitter kainate. A new method for quantitatively measuring the spatiotemporal size of the waves is described. This measure results in a power law distribution of wave sizes, meaning that the process that creates the waves has no preferred spatial or temporal (size or lifetime) scale. This power law is one signature of self-organized critical phenomena, a class of behaviors found in many areas of science. The physiological results for glial networks are fully supported by numerical simulations of a simple network of noisy, communicating threshold elements. By contrast, waves observed in astrocytes cultured from human epileptic foci exhibited radically different behavior. The background random activity, or "noise", of the network is controlled by the kainate concentration. The mean rate of wave nucleation is mediated by the network noise. However, the power law distribution is invariant, within our experimental precision, over the range of noise intensities tested. These observations indicate that spatially and temporally coherent Ca2+ waves, mediated by network noise may play and important role in generating correlated neural activity (waves) over long distances and times in the healthy vertebrate central nervous system.

Astrocytes↗
PubMed1997

Alterations in sympathetic innervation of thymus and spleen in aged mice.

Age is associated with reduced immune reactivity, contributing to increased rates of infectious disease and cancer in old age. We have begun to assess the potential for sympathetic nervous system involvement in age-related immune dysfunction by characterizing sympathetic noradrenergic (NA) innervation in lymphoid organs in old animals. In the present study noradrenergic innervation of spleen and thymus was examined histologically and neurochemically in 2-, 12- and 24-month old BALB/c mice. In the thymus of 2-month old animals, NA nerve fibers were found in the subcapsular, cortical, and cortico-medullary regions associated with blood vessels and septa; occasional branches from these nerve fibers entered the parenchyma. With increasing age and thymic involution, NA nerve fibers increased in density; by 24 months of age, dense plexuses were compacted among septa and blood vessels, and numerous linear, varicose nerve fibers were observed branching into the parenchyma. Thymic norepinephrine (NE) concentration (per mg wet weight) increased approximately 4-fold in 12-month old animals and 15-fold in 24-month old animals. Taking the reduced thymus weight into account, total thymic NE at 12- and 24-month of age was equivalent to total thymic NE at 2-month of age, suggesting that NA innervation is maintained as the thymus involutes. In the spleen from 2-month old animals, NA innervation entered the white pulp with the central artery to innervate the periarteriolar lymphatic sheath and the marginal zone. At 12-month of age, histologically and neurochemically there was no change in splenic NA innervation. By 24-month of age, NE was increased significantly, independent of changes in spleen weight. Histologically, increased catecholamine-containing fibers were apparent at 24-month of age, particularly in the parenchyma surrounding the central artery. The alterations in sympathetic NA innervation of lymphoid organs with age suggest that the sympathetic nervous system and NE may play a role in age-associated immune dysregulation. Alternatively, the changes in NA innervation may be secondary to functional changes within the immune system.

Age Factors↗
PubMed1996

Norepinephrine in mouse spleen shows minor strain differences and no diurnal variation.

Strain differences have been invoked to explain differing results when studying neural-immune interactions in laboratory animals. We investigated the splenic norepinephrine (NE) content and concentration in three strains of male mice (BALB/C, C57BL/6, and DBA/2), as well as possible diurnal variability in this innervation. Diurnal plasma corticosterone levels served as a positive control. Mice were housed on a 12 h on/12 h off light/dark cycle for 3 weeks, then sacrificed at one of six times during the 24 h cycle. Spleen NE total content and concentrations were determined using high performance liquid chromatography with electrochemical detection. We found small but significant differences between strains in total resting spleen NE content (BALB/C > C57BL/6 > DBA/2) and in resting NE concentration (C57BL/6 > BALB/C > DBA/2). This may reflect differences in spleen weight (BALB/C > DBA/2 > C57BL/6). The expected diurnal pattern of plasma corticosterone was seen in all strains, but no diurnal differences were found in NE content or concentration.

Animals↗
PubMed1995

Fluorenylalkanoic and benzoic acids as novel inhibitors of cell adhesion processes in leukocytes.

A series of fluoren-9-ylalkanoic and alkylbenzoic acids was prepared as simplified analogues of a previously reported series of antiinflammatory agents which act to inhibit neutrophil recruitment into inflamed tissue. The previous compounds ("leumedins") contained (alkoxycarbonyl)amino or benzoic acid moieties tethered to a fluorene ring. This functionality was replaced with simple structural elements. The new compounds were, in general, found to be more potent than the earlier series at inhibiting adherence of neutrophils to serum-coated wells or endothelial cells in vitro. Compound 9 was approximately 10-fold more potent than the previously reported FMOC-phenylalanine, of which it is an analogue. Similarly, compound 19 was superior in potency to its first generation progenitor, NPC 16570. The new compounds were shown to inhibit neutrophil adherence under conditions in which adherence is mediated by Mac-1 (CD11b/CD18) and LFA-1 (CD11a/CD18); they thus appear to target beta 2-integrins in their antiadhesion activity. These compounds provide a departure point for the further development of new cell adhesion inhibitors which should exhibit enhanced potency and a more selective mode of action.

Benzoates↗
PubMed1995

Catecholamine influences and sympathetic neural modulation of immune responsiveness.

Primary and secondary lymphoid organs are innervated extensively by noradrenergic sympathetic nerve fibers. Lymphocytes, macrophages, and other cells of the immune system bear functional adrenoreceptors. Norepinephrine fulfills criteria for neurotransmission with cells of the immune system as targets. In vitro, adrenergic agonists can modulate all aspects of an immune response (initiative, proliferative, and effector phases), altering such functions as cytokine production, lymphocyte proliferation, and antibody secretion. In vivo, chemical sympathectomy suppresses cell-mediated (T helper-1) responses, and may enhance antibody (T helper-2) responses. Noradrenergic innervation of spleen and lymph nodes is diminished progressively during aging, a time when cell-mediated immune function also is suppressed. In animal models of autoimmune disease, sympathetic innervation is reduced prior to onset of disease symptoms, and chemical sympathectomy can exacerbate disease severity. These findings illustrate the importance of the sympathetic nervous system in modulating immune function under normal and disease states.

Animals↗
PubMed1994

Sympathetic nervous system modulation of the immune system. II. Induction of lymphocyte proliferation and migration in vivo by chemical sympathectomy.

We have used chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in adult mice to study the role of the sympathetic nervous system (SNS) in regulating cellular proliferation and migration in lymphoid organs. Following sympathectomy, an increase in inguinal and axillary lymph node (LN) weight and cellularity was observed. This increase paralleled increased cellular proliferation in vivo, as measured by uptake of [125I]deoxyuridine (125IUdR). Transient increases in cellular proliferation also were observed in spleen and bone marrow following sympathectomy. Administration of desipramine prior to 6-OHDA to prevent sympathectomy resulted in control levels of proliferation. beta-Adrenoceptor blockade just prior to or following 6-OHDA treatment did not alter the enhanced proliferation. Migration of normal 51Cr-labelled lymphocytes into inguinal and axillary LN was enhanced in sympathectomized recipients. Conversely, cells from sympathectomized animals showed diminished migration to these LN upon transfer into intact recipients. These results demonstrate that depletion of NA innervation alters cellular proliferation and lymphocyte migration in primary and secondary lymphoid organs.

Animals↗