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PubMed1989

Immunomodulators and feeding regulation: a humoral link between the immune and nervous systems.

Cells of the nervous and immune systems have specific receptors for humoral substances that originate in both systems. These elements establish a bidirectional information exchange network between the nervous and immune systems. In particular, neuroregulators (neurotransmitters and neuromodulators) can modulate specific immune system function(s) and immunoregulators (immunomodulators) can modulate specific nervous system function(s). Modulation of immune functions by neuroregulators has been receiving considerable attention; however, modulation of nervous system functions by immunomodulators has been little studied. The presence of immunomodulators in the brain and cerebrospinal fluid may represent local synthesis by astrocytes, microglia, endothelial cells, intrinsic macrophages and blood-derived lymphocytes which cross the blood-brain barrier, or the concentration of substances derived from the peripheral blood. Acute and chronic inflammatory processes, malignancy, and immunological reactions stimulate the synthesis and release of immunomodulators in various cell systems. These immunomodulators have pivotal roles in the coordination of the host defense mechanisms and repair and induce a series of endocrine, metabolic, and neurologic responses. This paper focuses on the effects of immunomodulators (interleukins, tumor necrosis factor, tuftsin, platelet activating factor, and others) on the central nervous system (CNS), in particular, on feeding regulation. It is proposed that an immunomodulatory system regulates food intake by a direct action in the CNS through a specific neuro-immuno interaction. This regulatory system may be operative during acute and chronic disease.

Animals↗
PubMed1990

Hypophysectomy and growth hormone replacement effects on multiple immune responses in rats.

Male Fischer 344 rats were hypophysectomized at 8 weeks of age. At 10 weeks of age, one group of these animals was treated with 40 micrograms of bovine somatotropin given daily sc for 13 days. A third group was sham-operated and injected daily with saline. All animals were sacrificed on Day 14 and multiple immune responses were assessed in each rat. Immune responses assayed included specific antibody production and delayed-type hypersensitivity (DTH) reactions to antigen, natural killer (NK) cell cytotoxicity, and production of interleukin 2 (IL2). Body and lymphoid organ weights, hematologic parameters, and spleen cell numbers were also recorded. Hypophysectomized (Hx) rats had reduced antibody synthesis, DTH reactions, NK cytotoxicity, IL2 (or IL4) production, body and organ weights, rbc counts, packed cell volumes, and hematocrits compared to sham-operated controls. White blood cell counts were elevated. Treatment of Hx animals with GH restored antibody and IL2 production and thymic weights and partially restored DTH reactions. These data indicate the pituitary is important in maintaining normal immune functions, and part of this effect may be via production of GH. It is postulated that GH may act through stimulation of IL2 (or IL4).

Animals↗
PubMed1990

Activation of rat peritoneal mast cells in coculture with sympathetic neurons alters neuronal physiology.

Rat peritoneal mast cells (PMC) were activated with anti-IgE or 48/80 while in coculture with neurons dissociated from mouse superior cervical ganglia. At 18-24 h of coculture, microelectrode recordings from neurons were made 15 min after activation of PMC with anti-IgE antibody or the secretagogue compound 48/80. These recordings showed that PMC activation caused depolarization of the neurons and decreased their membrane resistance. Both methods of activation resulted in similar changes in these neuronal characteristics. The resting potential decreased by an average of 15% from the control value of -36.0 +/- 0.6 mV (SEM) (n = 121). The membrane resistance decreased by an average of 60% from the control value of 34.2 +/- 2.0 M omega (n = 75). Application of PMC secretion products directly onto neuronal somata caused reversible changes similar to those caused by activation of cocultured PMC. A decrease in membrane resistance that was observed in neurons cocultured with PMC for 18-24 h without stimulation was due to a proportion of PMC undergoing spontaneous activation. These changes in neuronal physiology are attributed to the action of substances released from the mast cells. This coculture model offers the means to study the cellular interactions involved in neuroimmune communication.

Action Potentials↗
PubMed1990

Demonstration of immunoreactive vasoactive intestinal peptide (IR-VIP) and somatostatin (IR-SOM) in rat thymus.

In the present work we demonstrate immunohistochemically the presence of both immunoreactive vasoactive intestinal peptide (IR-VIP) and immunoreactive somatostatin (IR-SOM) cells in the thymus of neonatal and adult rats. IR-VIP and IR-SOM from thymic tissue extracts were identified by gel chromatography, HPLC as VIP standard, and somatostatin S-28, respectively. IR-VIP (352.7 pg/thymus) amounts greater than those of IR-SOM (38.7 pg/thymus) detected by radioimmunoassay in the thymus of 3-month-old rats reflected the abundance of IR-VIP positive cells demonstrated by immunohistochemistry. Somatostatin-like immunoreactive cells were identified as epithelial or neuroendocrine-like cells arranged in the thymic cortico-medullary border, whereas IR-VIP positive cells appeared to be large lymphoid cells distributed along the connective tissue trabeculae. Furthermore, IR-VIP lymphoid cells occurred in the periarteriolar lymphoid tissue of the splenic white pulp where lymphoblasts accumulate. The results are discussed with respect to the mutual interactions between the neuroendocrine and immune systems and the possible role played by neuropeptides in these interactions.

Animals↗
PubMed1990

Effects of immobilization stress on the pathogenesis of acute murine toxoplasmosis.

Stress modulates a variety of immune responses. We investigated the effects of immobilization stress on the pathogenesis of acute murine toxoplasmosis, an infection in which cell-mediated immunity is of major importance in host defense. Repetitive overnight immobilization beginning 3 days prior to infection enhanced (p less than 0.05) the mortality of mice infected with a virulent strain (C56) of Toxoplasma gondii (77% vs 15% mortality in restrained and control mice, respectively). Daily immobilization for 14 days prior to infection abrogated (p less than 0.05) the lethal effect of immobilization, suggesting an adaptive mechanism. To explore the effect of immobilization with a less virulent strain, the Me49 strain of T. gondii was studied. Acute infection with T. gondii Me49 resulted in anorexia and weight loss, while spleen size and respiratory burst activity of peritoneal exudate cells were enhanced (p less than 0.01). Immobilization (twice daily for 2 h) did not significantly alter survival or other clinical features of acute T. gondii infection. In addition, immobilization suppressed (p less than 0.05) phorbol myristate acetate-stimulated release of superoxide anion by peritoneal exudate cells in healthy naive mice, but not in infected mice. These findings indicate that immobilization stress can alter the pathogenesis of acute T. gondii infection in healthy mice, but the effect of this stress paradigm will be influenced, in part, by the timing of the immobilization and the virulence of the strain of T. gondii.

Animals↗
PubMed1990

Differential effects of beta-endorphin on cAMP levels in human peripheral blood mononuclear cells.

In the present paper we demonstrate that one of the early effects of the opioid peptide beta-endorphin on human peripheral blood mononuclear cells is the induction of a change in the intracellular cAMP level. However, the effect of beta-endorphin on cAMP levels is not uniform; increases as well as decreases in cAMP level are observed. It appears that beta-endorphin is a true modulator of intracellular cAMP level: the peptide will increase cAMP levels in cells with a low baseline level. In contrast, beta-endorphin tends to decrease cAMP levels is cells with a high cAMP concentration. Moreover, beta-endorphin modulates the rise in cAMP induced by beta-adrenergic activation. The effect of beta-endorphin on cAMP level correlates negatively with the magnitude of the change in cAMP level induced by beta-adrenergic activation.

Adult↗
PubMed1990

Neuropeptide-immunoreactive cells in human thymus.

The outer cortex of the human thymus contains a one- to two-cell-thick layer that is immunoreactive with antisera against beta-endorphin, (Leu)- and (Met)-enkephalin, bombesin, and substance P. The epithelial nature of these immunostained cells is revealed by immunoelectron microscopic studies showing the presence of desmosomal junctions. The presence of peptide-containing cells in the outer cortex, where the most immature and recently immigrated thymocytes are found, emphasizes the role of neuropeptides in regulating the microenvironment for T cell development.

Cell Differentiation↗
PubMed1990

Beta-endorphin's modulation of lymphocyte proliferation is dose, donor, and time dependent.

We find that beta-endorphin (Bend) can have, positive, negative, or neutral dose-dependent effects on the mitogen-stimulated proliferation of human peripheral blood lymphocytes. The distribution of positive, negative, or neutral responses was nonrandom. In studies carried out over a year, we show that an individual's mitogen-stimulated lymphocyte proliferative response to Bend can change with time. We show that the inhibition induced by cortisol can be, in part, relieved by Bend. On the basis of our results and those of others in the field, we put forward a model that can qualitatively account for many of the observations we and other investigators have made.

Adult↗
PubMed1990

Self-stimulation behavior: consequences upon immunity?

A variety of behavioral and emotional factors can affect the immune response by changing the brain immunoregulatory mechanisms, resulting in immunosuppression or immunopotentiation. This experiment deals with the effect of chronic self-stimulation behavior on the immune response and lymphoid tissue. Male rats were stereotaxically implanted with bipolar electrodes into the lateral hypothalamus and 7 days after surgery were screened for self-stimulation behavior. Lateral hypothalamus self-stimulating rats (LH-SS) were allowed to self-stimulate for 60 min/day for a period of 9 consecutive days: 5 days before and 4 days after immunization with 5 x 10(9) sheep red blood cells (SRBC). The animals were sacrificed and plaque-forming cell assay (PFC), microhaemmagglutination reaction with SRBC, and differential blood leucocyte counts were performed. The thymus, spleen, and inguinal lymph nodes were weighed and processed for histological examination. In the LH-SS group, an enhanced PFC response and increased anti-SRBC antibody titer were observed when compared to controls. The thymus and spleen of LH-SS rats were smaller in size in comparison with controls, but only with moderate changes in splenic cellular make-up. The relative number of lymphocytes was increased in peripheral blood of LH-SS rats when compared to intact animals. The results obtained suggest that chronic self-stimulation behavior can modulate some parameters of humoral immune response and affect the relative weight of lymphoid organs in the rat.

Animals↗
PubMed1990

Circadian analysis of mononuclear cells in the rat following pinealectomy and superior cervical ganglionectomy.

The role of the pineal gland and adrenocorticosteroids in circadian rhythmicity of immune function was investigated in Sprague-Dawley rats that either had been pinealectomized (PX) or had undergone superior cervical ganglionectomy (SCGX), which functionally denervates the pineal. For both experiments, conducted between August and October, rats were entrained to a 10-h light:14-h dark cycle and fed ad libitum. The circadian rhythm in monocytes (ANOVA, p less than .01 for Control + Sham + PX samples) tended to parallel that of plasma corticosteroid levels (ANOVA, p less than .01) with the peak during early dark and the nadir at early light. In comparison, suppressor/cytotoxic T cells and B cells tended to be more frequent during early light with minimum levels during early dark (ANOVA, p less than .05 and .01, respectively, for Control + Sham + PX samples). Natural killer (NK) activity in control animals varied significantly (ANOVA, p less than .05) over the light:dark cycle with peak activity during early dark in the SCGX experiment, but was only slightly elevated during late dark in the PX experiment. PX animals exhibited increased frequency of NK cells, but only in samples collected during the day (t test, p less than .05). This effect was not observed in sham-operated PX controls and in SCGX animals. Neither PX nor SCGX had a significant (ANOVA) effect on plasma corticosterone levels. These observations in the rat are consistent with findings in mice and humans that corticosteroids play an important general role in circadian rhythmicity of immune functions. In contrast, the present study suggests that pineal gland influence of immune function(s) is more specific and that pineal gland interaction with NK cells has a circadian component.

Animals↗
PubMed1990

A neuroimmunoregulatory-like mechanism responding to stress in the marine bivalve Mytilus edulis.

Mytilus edulis has been the subject of recent studies to determine whether the relationship between the immune and nervous systems seen in vertebrates also exists in invertebrates. In the present study the effects of experimentally induced "stressful" stimuli on immunoactive hemocytes were studied in this mollusc. This subpopulation of invertebrate blood cells, resembling vertebrate granulocytes, has been previously shown to produce and react to opioid peptides. Their activation, like that of vertebrate immunocytes, expresses itself in distinctive conformational changes preceding cellular mobilization. The cellular response to "stress" observed is the same as that to the administration of exogenous mammalian opioid peptides. This strongly suggests that under the conditions of stressful stimuli, the immune/defense system can be altered by endogenous neuropeptides. The involvement of opioids in neuroimmunoregulatory phenomena appears to have a long evolutionary history.

Animals↗
PubMed1991

Innervation of the rat thymus gland.

Current views from different laboratories on the innervation of the thymus gland are reviewed with particular reference to the rat. Noradrenergic nerve profiles of the sympathetic nervous system have been demonstrated in the subcapsular cortex, at the corticomedullary junction and in the cortex itself, and extremely sparsely in the medulla. By following beta-adrenergic receptor development in postnatal rats, it has been shown that there is a marked increase in density and morphological organization of the receptor in the medulla with the maturation of thymocyte function (monitored by measuring the proliferation response to concanavalin A) and a sexual dimorphism during the ontogeny of the receptor. Chemical sympathectomy of adult rats with 6-hydroxydopamine (6-OHDA) or guanethidine resulted in a loss of thymus weight, decreased cellularity, and increased apoptosis but a rise in the numbers of proliferating cells in the cortex. By contrast, proliferation of peripheral T cells was reduced after the use of 6-OHDA. Chemical sympathectomy also demonstrated that there were at least three nerve nets in the gland: noradrenergic neural profiles that were destroyed with both 6-OHDA and guanethidine, vasoactive intestinal polypeptide (VIP)-positive profiles that persisted, and AChE- and CGRP-positive profiles and cells that also persisted but had a different distribution to VIP-positive fibers. Some functional correlates of thymic innervation are discussed although the subject now needs to be further researched.

Acetylcholine↗
PubMed1991

Substance P innervation of spleen in rats: nerve fibers associate with lymphocytes and macrophages in specific compartments of the spleen.

We investigated the distribution of SP+ nerve fibers in the spleen of adult male Fischer 344 rats. SP+ nerve fibers entered the spleen with the splenic artery in the hilar region, arborized along the venous sinuses, and extended from these larger plexuses into trabeculae and the surrounding red pulp. In the white pulp, SP+ nerve fibers were found in the marginal zone, and in the outer regions of the PALS among T lymphocytes. No SP+ nerve fibers were observed in association with the splenic capsule, the central arteries of the white pulp, or the follicles. SP levels in rat spleen were 5.7 +/- 0.4 ng/g wet wt. On the basis of the present findings of SP presence in nerve fibers in the spleen, and published evidence for SP receptors on lymphocytes and macrophages, we suggest that SP derived from nerve fibers in the spleen can act as a neurotransmitter with cells of the immune system as targets. These SP nerve fibers may be an important neural link between the nervous system and the immune system and may participate in modulation of immune reactivity and inflammatory responses.

Animals↗
PubMed1991

The neuroimmune connection in human tonsils.

The present light microscopic immunohistochemical study evaluates the distribution of peptidergic nerve fibers in human tonsil and describes their spatial relationship with specific cells of the immune system. Further, using a panneural marker protein gene product (PGP) 9.5, a qualitative evaluation of the density of specific peptidergic innervation of the human tonsil was performed. Nerve fibers staining for tachykinins, calcitonin gene-related peptide, neuropeptide Y, or vasoactive intestinal polypeptide/peptide histidine isoleucine showed characteristic distribution patterns, but constituted only a minor subfraction of the PGP 9.5-stained fiber population. Both peptide- and PGP 9.5-immunopositive fibers predominantly supplied the vasculature; nonvascular areas were less densely innervated. Double staining for surface antigens thought to be associated with subsets of lymphoid cells, i.e., T-cells, B-cells, granulocytes, and macrophages, and for peptides or PGP 9.5 revealed close proximity of characteristic subpopulations of neurochemically defined nerve fibers and the various immune cells. The presence of peptidergic nerve fibers among T-cells was more prevalent than peptidergic nerve fibers adjacent to macrophages. Few positively stained nerve fibers resided in B-cell compartments. Neuro-B-cell interrelations were extremely infrequent. Neuroimmune connections were restricted to paravascular, subepithelial, and interfollicular regions, while germinal centers were devoid of nerve supply. The results are compatible with the view that peptides, being present in small-diameter nerve fibers, could exert an indirect immunoregulatory role by influencing vascular tone and/or permeability. In quantitative terms, a direct neuroimmunomodulatory action of endogenous neurally derived peptides appears to be of minor importance, because nonvascular neuroimmune circuits were found infrequently and were regionally restricted. However, we cannot be sure that all fibers were stained. The functional state of the peptidergic and nonpeptidergic innervation of the human palatine tonsil may be of physiological and pathophysiological significance within the psycho-neuro-immuno-endocrine network. The peptide-coded neuroimmune link may play a role in tonsillar pain.

Biomarkers↗
PubMed1991

Interrelation of peptidergic innervation with mast cells and ED1-positive cells in rat thymus.

The peptidergic innervation of rat thymus has been investigated by immunohistochemical methods, focusing on the spatial interrelationship of peptidergic nerve fibers with mast cells and macrophages in the rat. An antiserum directed against the protein gene product 9.5 (PGP 9.5) regarded as a pan-neuronal marker revealed a rich innervation, especially in the subcapsular cortex, in interlobular septa, and of the vasculature in the cortex and the corticomedullary boundary. A minor proportion of PGP 9.5-immunoreactive (ir) fibers supplied the thymic parenchyma. The main component of peptidergic innervation consisted of fibers costaining for tachykinins (TKs) and calcitonin gene-related peptide (CGRP), but considerable amounts of neuropeptide Y (NPY)/tyrosine hydroxylase (TH)-positive fibers and vasoactive intestinal polypeptide/peptide histidine isoleucine-positive fibers also were present. There were sparse Leu-enkephalin and galanin immunoreactivities in thymic nerve fibers, while neurotensin was absent from nerve fibers. Close associations of TK/CGRP-ir and NPY-ir fibers with mast cells were frequently detected in the connective tissue areas of the thymus, often adjacent to the vasculature. TK/CGRP-ir fibers and some rare NPY-ir fibers were found adjacent to EDl-positive macrophages and less frequently to mast cells. TK/CGRP-ir and NPY-ir fibers were mainly detected in relation to the vasculature of the cortex and the corticomedullary boundary, but also were found in capsular and subcapsular regions of the thymic cortex. The possible importance of the close spatial relationship between the various peptide-containing nerve fibers and mast cells and ED1-positive macrophages in neuroimmune integration is discussed.

Animals↗
PubMed1991

The neuroimmune link in the bronchus-associated lymphoid tissue (BALT) of cat and rat: peptides and neural markers.

This light microscopic immunohistochemical study investigates the distribution and target interrelations of nerve fibers in bronchus-associated lymphoid tissues (BALT) of rat and cat by using antisera against (1) the polyneuronal marker protein gene product 9.5 (PGP 9.5), (2) selected opioid and nonopioid peptides, and (3) the marker enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). In both species, a similar distribution pattern of PGP, peptide, and catecholamine enzyme immunoreactive was observed. Anti-PGP 9.5 stained all nerve fibers (except some smaller, calcitonin gene-related peptide-immunoreactive (CGRP-ir) fibers presumably of the C-type) throughout the different compartments of BALT, e.g., under the epithelium, in the smooth muscle layer, along the vasculature, and between immune cells of BALT parenchyma. The distribution of fibers staining for peptides (substance P (SP), (CGRP), neuropeptide Y (NPY). Leu-enkephalin, Met-enkephalin-Arg-Gly-Leu) and/or the catecholamine enzymes was also not compartment-specific. However, the density of the different peptidergic fibers and those staining for the marker enzymes exhibited region- and target-specific variations, e.g., fibers, cocontaining substance P and CGRP were more ubiquitous in nonvascular regions than codistributed NPY-, TH-, and DBH-ir fibers, which clearly prevailed in perivascular plexus. Regularly, nerve fibers staining for any of the peptides and markers investigated formed close contacts with mast cells, cells of the macrophage/monocyte cell line (identified as ED1 + cells), and/or other lymphoid cells, although with different frequencies. We assume that the SP/CGRP innervation is mainly of primary sensory origin, while the NPY innervation is chiefly derived from postganglionic noradrenergic sympathetic neurons. The VIP/PHI component is most likely postganglionic cholinergic while the opioid component, apparently derived from the Proenkephalin precursor, could be of differential origin. We propose that the neuroimmune connections in BALT play a significant role in the regulation and/or modulation of physiological/pathophysiological mechanisms of the lung. BALT may also be an integral part of the psycho-neuro-immune axis.

Amino Acid Sequence↗
PubMed1991

Colocalization of immunoreactive oxytocin, vasopressin and interleukin-1 in human thymic epithelial neuroendocrine cells.

Monoclonal antibodies to oxytocin (OT) and vasopressin (VP) revealed some positively staining stromal cells in the subcapsular cortex and in the medulla of the human thymus. We further demonstrated that these cells are a subset of epithelial endocrine cells and also contain immunoreactive interleukin-1 together with the neuropeptides. In addition, the thymic cells stained by monoclonal antibodies directed to the cyclic part of oxytocin or vasopressin also contained some immunoreactive neurophysins. These data support the concept of intrathymic synthesis of neurohypophyseal-like peptides fitting the hypothalamic model. However, we observed that, contrary to the situation in the brain, OT- and VP-like peptides colocalized in the same thymic cells. Furthermore, one monoclonal antibody, specific for the tail part of oxytocin, did not label thymic cells. Therefore, thymic neuropeptide(s) could be related to, but distinct from, authentic OT and VP. These observations suggest some molecular differences between hypothalamic and thymic oxytocin biosynthetic pathways which need to be further investigated.

Antibodies, Monoclonal↗