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D L Felten

Publications and source records attributed to D L Felten.

At least 37 records · Page 2Linked to original sources
PubMed1998

Sympathectomy-induced immune changes are not abrogated by the glucocorticoid receptor blocker RU-486.

Removal of sympathetic noradrenergic input to the immune system by injection of 6-hydroxydopamine (6-OHDA) triggers increases in antigen-specific in vitro splenocyte proliferation and cytokine production in BALB/cJ and C57B1/6J mice. This examines the possible role of glucocorticoids in these previously reported changes. In both strains, chemical sympathectomy triggers an elevation of glucocorticoid levels immediately following injection of 6-OHDA, returning to normal within one to two days. In the BALB/cJ strain, glucocorticoid elevation is seen only after the initial 6-OHDA injection; levels in chronically denervated animals are not different from controls. In the C57B1/6J strain, the increase is seen even with chronically denervated animals. Prior implantation of mice with pellets containing the glucocorticoid receptor antagonist RU-486 does not abrogate denervation-induced increases in cytokine production or proliferation in either strain. In addition to the previously reported increased interleukin (IL)-2 and IL-4 production, there is an increase in IFN-gamma production in the C57B1/6J strain following either acute or chronic denervation. The persistence of denervation-induced changes even when the effect of corticosterone is blocked with RU-486 or diminished with chronic denervation indicates that the changes are driven mainly by a glucocorticoid-independent mechanism.

Animals↗
PubMed1998

Restoration of sympathetic noradrenergic nerve fibers in the spleen by low doses of L-deprenyl treatment in young sympathectomized and old Fischer 344 rats.

It is well-established that noradrenergic (NA) nerve fibers in spleen and lymph nodes influence cell-mediated immune responses. Such responses are diminished in young animals following chemical sympathectomy and in older animals accompanying an age-related decline in NA nerve fibers in spleen and lymph nodes. The purpose of this study was to determine whether treatment with deprenyl, an irreversible monoamine oxidase-B (MAO-B) inhibitor, would hasten the process of splenic NA reinnervation following chemical sympathectomy in young rats and would reverse the age-related loss of sympathetic NA fibers in the spleen of old rats. To examine the effects of deprenyl in young sympathectomized rats, 3-month-old male Fischer 344 (F344) rats were treated with 6-hydroxydopamine (6-OHDA) and administered 0, 0.25, 1.0, 2.5, or 5.0 mg deprenyl/kg body weight (BW)/day intraperitoneally (i.p.) for 1, 15, or 30 days. In another study, 21-month-old male F344 rats were treated with 0, 0.25, or 1.0 mg deprenyl/kg BW/day i.p. for 9 weeks. At the end of the treatment period, spleens were removed and NA innervation was assessed by fluorescence histochemistry, immunocytochemistry, and quantitation of norepinephrine (NE) by high performance liquid chromatography with electrochemical detection (HPLC-EC). In the spleens of young sympathectomized rats, there was faint fluorescence or absence of fluorescence and tyrosine hydroxylase-positive (TH+) fibers around the central arteriole and in the periarteriolar lymphatic sheath of the white pulp one day after administration of 6-OHDA, indicating a severe loss of NA innervation compared with unlesioned control animals. Treatment of sympathectomized rats with 1.0 mg, 2.5 mg, and 5.0 mg/kg deprenyl for 30 days increased the density of NA innervation estimated by both fluorescence histochemistry and immunocytochemistry compared with vehicle-treated controls recovering spontaneously from 6-OHDA. Splenic NE concentration was increased in the hilar region of sympathectomized rats treated with 2.5 mg and 1.0 mg/kg deprenyl after 15 and 30 days, respectively, compared with untreated and vehicle-treated sympathectomized rats. The spleens of untreated and saline-treated old rats showed a reduction in the density of NA innervation in the white pulp compared with young animals. Treatment of old rats for 9 weeks with 1.0 mg/kg deprenyl induced moderate to intense fluorescent fibers and linear TH+ nerve fibers around the central arteriole and in other compartments of the white pulp, and increased splenic NE concentration in the hilar region and NE content in the whole spleen. Taken together, these results provide strong evidence for a neurorestorative property of deprenyl on sympathetic NA innervation of the spleen, which may lead to an improvement in cell-mediated immune responses.

Adrenergic Fibers↗
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↗
PubMed1997

Corticosterone responses of adult Lewis and Fischer rats.

Indwelling catheters were implanted into the inferior vena cava of adult male and female Lewis/N and Fischer 344 rats. Each animal was exposed to ACTH, novelty stimulation, nicotine, lipopolysaccharide (LPS), and saline on 5 consecutive days. Blood was withdrawn before (baseline) and at several time points after the stimulus on each day. There were no differences in baseline corticosterone levels nor in responses to saline in any group. In general, responses to stimulation peaked at 15-30 min and returned to baseline by 60-90 min. Corticosterone responses to LPS showed a different time course; maximal responses occur at 1-2 h and return to baseline by 24 h. Fischer animals showed higher corticosterone levels than Lewis rats during the response to stimulation, but returned to baseline at the same times. Females of each strain showed higher corticosterone responses than males at 15, 30, and 45 min after ACTH, but the sexes did not differ in response to the other stimuli. For individual rats, the maximum response to ACTH was slightly correlated with the maximum response to novelty stimulation, nicotine, and saline but was not correlated with the response to LPS.

Adrenocorticotropic Hormone↗
PubMed1997

Vasoactive intestinal polypeptide (VIP) innervation of rat spleen, thymus, and lymph nodes.

In the thymus, VIP-positive (+) fibers were found in the capsular/septal system, cortex, and medulla. In the spleen, VIP+ nerves coursed along large arteries and central arterioles, and in the white pulp, venous/trabecular system, and red pulp. Splenic VIP innervation was more robust in Long-Evans hooded rats than in Fischer 344 rats. VIP+ nerves in mesenteric lymph nodes were found in the cortex, and along the cortical vasculature and medullary cords. No VIP innervation was observed in popliteal lymph nodes. Immunocytes also were VIP+, suggesting that both neural and cellular synthesis of VIP contributes to VIP concentration in lymphoid organs. Surgical sympathectomy did not alter splenic or thymic VIP content, respectively, and VIP innervation of these organs was not altered, suggesting an origin for VIP+ nerves other than the sympathetic nervous system.

Animals↗
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↗
PubMed1996

Conditioned increase in peripheral blood mononuclear cell (PBMC) number and corticosterone secretion in the rat.

Femoral artery catheters were surgically implanted into male Lewis/N rats to allow blood sampling and drug infusion in the freely moving animal. After recovery, conditioned animals received four pairings of a peppermint odor, the conditioned stimulus (CS), and an infusion of 0.1 mg/kg nicotine bitartrate, an unconditioned stimulus (US) for an increase in the number of peripheral blood mononuclear cells (PBMC) and an increase in corticosterone concentration. When reexposed to the peppermint odor, conditioned animals showed a significant increase in PBMC number and corticosterone secretion when compared to saline and unpaired control groups and previously conditioned animals that were not reexposed to the CS. Increased PBMCs were found on the fifth unreinforced CS trial. Conditioned CORT responses were lost after the initial test trial. The data indicate that the distribution of immune cells can be influenced by learning processes and support the role of learning in the regulation of corticosterone secretion.

Animals↗
PubMed1996

Application of 6-hydroxydopamine into the fatpads surrounding the draining lymph nodes exacerbates adjuvant-induced arthritis.

Adjuvant-induced arthritis (AA) was examined in Lewis rats following local injection of 6-hydroxydopamine (6-OHDA) into the fatpads of the popliteal and inguinal lymph nodes which drain the hindlimbs (DLN). This method of 6-OHDA treatment resulted in noradrenergic (NA) denervation of DLN, spleen, and other organs in the peritoneal cavity, while sparing NA nerve fibers in the hindlimbs. Sympathectomy exacerbated the inflammation and osteopathic destruction of arthritic joints. Significant increases in dorsoplantar width in arthritic rats following denervation were observed by day 27 following immunization compared to nondenervated arthritic animals. Radiographic evaluation on day 27 after immunization confirmed the inflammation of soft tissue and revealed deterioration of bones of the ankle joint in both AA groups compared with the control groups; more extensive joint damage was apparent in arthritic rats following denervation compared to nondenervated arthritic rats. These findings suggest that the NA innervation of DLN and spleen (and possibly other organs of the peritoneal cavity) plays a regulatory role in the expression of AA. These data supports the hypothesis that absence of NA innervation in lymphoid organs during initiation, onset, and progression of the disease results in exacerbation of AA.

Adipose Tissue↗
PubMed1996

The significance of vasoactive intestinal polypeptide (VIP) in immunomodulation.

Evidence for VIP influences on immune function comes from studies demonstrating VIP-ir nerves in lymphoid organs in intimate anatomical association with elements of the immune system, the presence of high-affinity receptors for VIP, and functional studies where VIP influences a variety of immune responses. Anatomical studies that examine the relationship between VIP-containing nerves and subpopulations of immune effector cells provide evidence for potential target cells. Additionally, the presence of VIP in cells of the immune system that also possess VIP receptors implies an autocrine function for VIP. The functional significance of VIP effects on the immune system lies in its ability to help coordinate a complex array of cellular and subcellular events, including events that occur in lymphoid compartments, and in musculature and intramural blood circulation. Clearly, from the work described in this chapter, the modulatory role of VIP in immune regulation is not well understood. The pathways through which VIP can exert an immunoregulatory role are complex and highly sensitive to physiological conditions, emphasizing the importance of in vivo studies. Intracellular events following activation of VIP receptors also are not well elucidated. There is additional evidence to suggest that some of the effects of VIP on cells of the immune system are not mediated through binding of VIP to its receptor. Despite our lack of knowledge regarding VIP immune regulation, the evidence is overwhelming that VIP can interact directly with lymphocytes and accessory cells, resulting in most cases, but not always in cAMP generation within these cells, and a subsequent cascade of intracellular events that alter effector cell function. VIP appears to modulate maturation of specific populations of effector cells, T cell recognition, antibody production, and homing capabilities. These effects of VIP are tissue-specific and are probably dependent on the resident cell populations within the lymphoid tissue and the surrounding microenvironment. Different microenvironments within the same lymphoid tissue may influence the modulatory role of VIP also. Effects of VIP on immune function may result from indirect effects on secretory cells, endothelial cells, and smooth muscle cells in blood vessels, ducts, and respiratory airways. Influences of VIP on immune function also may vary depending on the presence of other signal molecules, such that VIP alone will have no effect on a target cell by itself, but may greatly potentiate or inhibit the effects of other hormones, transmitters, or cytokines. The activational state of target cells may influence VIP receptor expression in these cells, and therefore, may determine whether VIP can influence target cell activity. Several reports described in this chapter also indicate that VIP contained in neural compartments is involved in the pathophysiology of several disease states in the gut and lung. Release of inflammatory mediators by cells of the immune system may destroy VIP-containing nerves in inflammatory bowel disease and in asthma. Loss of VIPergic nerves in these disease states appears to further exacerbate the inflammatory response. These studies indicate that altered VIP concentration can have significant consequences in terms of health and disease. In addition, the protective effects of VIP from tissue damage associated with inflammatory processes described in the lung also may be applicable to other pathological conditions such as rheumatoid arthritis, anaphylaxis, and the swelling and edema seen in the brain following head trauma. While VIP degrades rapidly, synthetic VIP-like drugs may be developed that interact with VIP receptors and have similar protective effects. Synthetic VIP-like agents also may be useful in treating neuroendocrine disorders associated with dysregulation of the hypothalamic-pituitary-adrenal axis, and pituitary release of prolactin.

Adjuvants, Immunologic↗
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

Noradrenergic and peptidergic innervation of lymphoid organs in the beluga, Delphinapterus leucas: an anatomical link between the nervous and immune systems.

The presence of peptidergic and noradrenergic sympathetic nerve fibers in specific compartments of both primary and secondary lymphoid organs of the rodent is well established. These nerve fibers directly contact lymphocytes and macrophages, as well as vascular and trabecular smooth muscle. We investigated the noradrenergic and neuropeptide-Y innervation of lymphoid organs in the cetacean, Delphinapterus leucas (beluga whale). The spleen, thymus, tonsil, gut-associated lymphoid tissue, and assorted lymph nodes were collected from five belugas, obtained during sanctioned hunts, and processed for catecholamine fluorescence histochemistry and for tyrosine hydroxylase and neuropeptide-Y immunocytochemistry. Innervation studies revealed fluorescent nerve fibers, tyrosine hydroxylase, and neuropeptide-Y positive nerve fibers in parenchymal lymphoid compartments, where they were closely associated with cells of the immune system, and in vascular and trabecular compartments. In lymphoid zones, tyrosine hydroxylase and neuropeptide-Y positive nerve fibers were observed in the periarteriolar lymphatic sheath and marginal zone of the spleen; in the outermost portion of the cortex, the corticomedullary zone, and medulla of the lymph nodes; in the parafollicular zones, and diffuse lymphocyte layer below the epithelium of the tonsil; in the outermost portion of some thymic lobules; and in the lamina propria of the gut. These findings are similar to those described for other mammals and substantiate an anatomical link between the nervous and immune systems in the beluga, whereby central nervous system activity may influence autonomic outflow to lymphoid organs and effect immunologic reactivity.

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↗
PubMed1994

Sympathetic nervous system modulation of the immune system. III. Alterations in T and B cell proliferation and differentiation in vitro following chemical sympathectomy.

Functional changes in lymph node (LN) and spleen lymphocytes were examined following sympathetic denervation of adult mice with 6-hydroxydopamine (6-OHDA). Sympathectomy reduced in vitro proliferation to concanavalin A (ConA) by LN cells and decreased LN Thy-1+ and CD4+ T cells. At the same time, ConA-induced interferon-gamma (IFN-gamma) production was increased, but interleukin-2 (IL-2) production was not altered. After sympathectomy, lipopolysaccharide (LPS)-stimulated proliferation of LN B cells was enhanced, in parallel with an increase in the proportion of sIgM+ cells. LPS-induced polyclonal IgM secretion was decreased, whereas polyclonal IgG secretion was dramatically enhanced. In the spleen, ConA and LPS responsiveness was reduced after sympathectomy, as was IL-2 and IFN-gamma production. The decreased proliferation was not associated with changes in splenic T and B cell populations. The uptake blocker desipramine prevented the 6-OHDA-induced changes in spleen and LN, indicating that these alterations were dependent upon neuronal destruction. These results provide evidence for heterogeneity of sympathetic nervous system regulation of T and B lymphocyte function and for organ-specific influences on immune function.

Animals↗