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Heavy metals and neuroimmunomodulation in Mytilus edulis.

Immunocytes of mussels are the chief immune defense in these organisms. When an immunocyte becomes activated there is a conspicuous change in its morphology (i.e., from round to amoeboid) that can be quantified using image analytical tools. Active immunocytes will typically show larger perimeters and areas and a smaller shape factor. Immunocytes exposed to heavy metals become inactive (Cd, Hg and Pb) thus with smaller perimeters (e.g., Pb2+ 2 ppm: P = 69.72 micron) and areas (e.g., Pb2+ 2 ppm: A = 270 micron2) and larger shape factors (Pb2 2 ppm: SF = 0.65) than the unexposed control cells (alpha = 0.05). Xenobiotics may also interfere with neuroimmunomodulation processes such as nitric oxide (NO) release. The release of NO is catalyzed by a calcium dependent constitutive nitric oxide synthase (cNOS). Presently, we are exploring the effects of heavy metals and other pollutants on cNOS activity, measured as real time NO release, in immunocytes and pedal ganglia from M. edulis. Preliminary results suggest that immunocytes exposed to Pb2+ (5 ppm) cause NO release and does not seem to inhibit further NO release in the presence of morphine. The possible implications of NO mediated Pb2+ neurotoxicity are also explored.

Animals↗

[New data about neuroimmunomodulation and its functional implications].

After a brief presentation of the immune system as sensorial and effector organ, which recognizes and defends against cellular aggressions, the main psychoneuroendocrine components of immune reaction regulation and modulation are shown. Both central nervous structures that control the hormonal emissions, the vegetative innervation of the lymphoid organs as wells as the afferent neurohumoral pathways involved in the making of the self-regulating and neuromodulating circuits of the humoral and cellular immune responses are mentioned. An important position is held by the interrelations between the hypothalamus-pituitary-corticoadrenal gland, the sympathetic-parasympathetic efferent pathways and the chemical messengers (hormones, neurotransmitters, interleukins, neurotrophins) which make possible the bi-directional neuroimmune communication for maintaining the homeostatic balances on this third effector pathway, too. Also experimental proof concerning the ability of central neurons to secrete neuromodulator cytokines and the presence of specific receptors for the various neuroactive molecules within lymphoid organs and circulating lymphocytes are presented. To close, the psychoemotional components of the neuroimmunomodulator circuits are mentioned, using as examples the changes induced by stress generally and oxidative stress in particular.

Animals↗

Neuroimmunomodulation in the intestinal mucosa.

The intestine contains major subdivisions of the nervous and immune systems. The lymphoid compartments of the intestine contain functionally distinguishable populations of immunologic cells and are innervated differently. The lamina propria has an extensive network of nerves using the neuropeptides SOM, SP, and VIP. Subpopulations of T cells, B cells, cells of the monocyte/macrophage line, and several other immunologically relevant cells have the ability to recognize and respond to these neuropeptide signals. SOM, SP, and VIP can act as potent regulators of lymphoid cell proliferation and interleukin and immunoglobulin production. The unusual effector lymphocytes in the epithelial layer of the intestine can be exposed to SP and VIP, and their responses may be regulated by these peptides. In the organized lymphoid compartments such as Peyer's patches, the neuropeptides VIP and SP may regulate the accumulation or recirculation of affector lymphocytes from the central compartment of the immune system and their subsequent response to antigens. The large array of immunoregulatory effects that have been found with these neuropeptides suggest that local neurophysiologic signals in the intestinal lymphoid microenvironments can regulate selected aspects of immune responses. The intestine is likely to be a highly specialized venue for neuroimmunomodulation in intact animals, and this has important implications in the physiologic and pathologic responses of the gut. Further investigations of these regulatory pathways will lead to new concepts concerning neural-immune interactions in general and the regulation of mucosal immunology in particular.

Animals↗

[Neuroimmunomodulation. The bi- and unilateral correlations between the nervous system and the immune system].

The nervous system-immune system relationships, namely the modulatory effects of the former upon the latter and vice versa, have been considered both in physiological and pathological conditions. The nervous system communicates with the immune system in two biochemical ways, by means of neurohormones and neurotransmitters, using anatomical and functional pathways related to the pituitary system (the manifold endocrine axes between hypophysis and peripheral endocrine glands) and autonomic system (especially the orthosympathetic one, and to much lesser extent the parasympathetic system). The immune system is able to modulate some nervous functions via cytokines, peptidic molecules produced by immunocytes, that can also be secreted in certain conditions by neural cells, such as astrocytes, microgliocytes and even neurons. The knowledge of physiology of the neuroimmunomodulation and related pathological changes may be very useful for understanding the pathogenesis and the pathophysiology of neuroimmunological diseases, and for their diagnosis and treatment.

Animals↗

Neuroimmunomodulation and psychoneuroendocrinology: recent findings in adults and aged.

In recent years the relationships among immune, endocrine and nervous systems have been extensively studied, and grouped in a new research field: psychoneuro-immunoendocrinology. Since ancient times its has been known that, in humans, mood as well as environmental influences could affect health. In the late '70s, only, evidence of bi-directional pathways has been achieved, first in animal models and, later on, in humans. We reviewed current knowledge on neuroimmunomodulation, concerning the influence of stress and psychological status on immunity as well as neuroendocrine modulation by the immune system, reporting some data obtained from our studies. Particularly, having detected a relevant impairment concerning most of the parameters studied, we emphasized the effects of depressive disorders on immune function in the elderly.

Adult↗

Anticancer neuroimmunomodulation by pineal hormones other than melatonin: preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin.

Despite several years of experimental observations, the clinical application of the neuroimmunomodulation is still at the beginning. The pineal gland plays a main role in mediating the link between psychoneuroendocrine and immune systems. Melatonin (MLT), which is the main pineal hormone produced during the night, has appeared to amplify IL-2 anticancer activity. Other pineal hormones, however, would have immunomodulatory activity, in particular 5-methoxytryptophol (5-MTT), which is mainly produced during the light phase of the day. Previous clinical studies have shown that low-dose IL-2 plus MLT may have therapeutic efficacy in advanced cancer patients with neoplasms generally resistant to IL-2 alone, with a tumor regression rate generally less than 20% and an acceptable toxicity. The present study was carried out to evaluate the efficacy of low-dose IL-2 in association with both MLT and 5-MTT. The study included 14 untreatable advanced solid tumor patients (lung cancer: 4; gastric cancer: 3; mesothelioma: 2; hepatocarcinoma: 2; pancreatic cancer: 1; melanoma: 1; colon cancer: 1). IL-2 was injected subcutaneously at 3 MIU/day for 6 days/week for 4 weeks, by repeating a second cycle after a 21- day rest period. Both MLT and 5-MTT were given orally at 40 mg/day in the evening and at 1 mg/day at noon. The clinical results, as evaluated by WHO criteria after each cycle, consisted of partial response (PR) in 4/14 (29%) (lung cancer: 2; hepatocarcinoma: 1; mesothelioma: 1), stable disease (SD) in 6 and progressive disease in the last 4 patients. The treatment was extremely well tolerated in all patients, and in particular no fever greater than 38 degrees C occurred. These preliminary results show that the neuroimmunotherapy with low-dose IL-2 plus two pineal hormones, MLT and 5-MTT, is a well tolerated and potentially effective cancer therapy of untreatable advanced solid tumor patients, with results apparently superior with respect to those previously described with IL-2 plus MLT alone.

Adjuvants, Immunologic↗

Neuroimmunomodulation of natural killer (NK) cells by ergot alkaloid derivatives.

Ergot alkaloids (EAs), products of Claviceps spp., are widely used in various fields of clinical medicine (neurology, psychiatry, endocrinology). In the present work we studied the neuroimmunomodulative effect of EAs on activation of NK cells and their signalling pathways. Furthermore, the killing capability of rat NK cells in vitro was examined in the presence of glycosidic derivatives of elymoclavine, agroclavine, and liposome-encapsulated EAs. The engagement of appropriate NK cell membrane receptors by EAs cause an indirect enhancement of adenylyl cyclase system through inhibition of G-protein al,2-subunit (up to 50 % of control values). All of the tested EAs enhanced the rat NK cell-mediated cytotoxic activity in vitro, particularly against target cells of astrocyte origin (C-6 glioma). The present results argue for a possible EA immunomodulatory role of cell-mediated immunity in tumour regression processes.

Animals↗

Hypothalamic-immune interactions. Effect of hypophysectomy on neuroimmunomodulation.

Electrolyte destruction of certain nuclei of the brain cause specific structural and functional changes in the immune system. Lesions in the preoptic-anterior hypothalamic area result in thymic involution and a decrease in the number and blastogenic reactivity of splenocytes. In contrast, lesions in the hippocampus increase thymic and splenic mitogenic responsiveness and cellularity. Hypophysectomy abrogates all changes in splenocyte number and function induced by hypothalamic and limbic lesions. The effects of ablating the hippocampus and amygdaloid complex on thymocyte number and function also are abolished. Hypothalamic lesions in hypophysectomized animals result in an increase in the number of thymocytes but suppressed mitogenic activity. These data indicated that neuroimmunomodulation is mediated predominantly but not exclusively by the pituitary gland.

Animals↗

Multiple neuropeptides in nerves supplying mammalian lymph nodes: messenger candidates for sensory and autonomic neuroimmunomodulation?

By the use of light microscopic (LM) immunohistochemistry, the presence of peptides and of dopamine beta-hydroxylase (DBH) in nerves supplying mammalian (guinea pig, rat, cat, pig, mouse, human) lymph nodes were examined. In all species, lymph nodes of various somatic and visceral regions were found to contain nerve fibers which stained for neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), substance P (SP), calcitonin gene-related peptide (CGRP) or DBH. SP- and CGRP-immunoreactive (ir) fibers completely overlapped and exhibited the widest distribution. They were present in perivascular, paravascular and many non-vascular fibers travelling in close contact with lymphoid cells. In contrast, NPY-ir fibers coincided with those staining for DBH, prevailed in perivascular plexus and only rarely branched off into lymphoid parenchyma. Alternate staining of adjacent sections revealed that SP/CGRP-ir fibers were different from NPY/DBH-ir fibers. The distribution of VIP-ir fibers was identical to that of PHI-ir fibers and partially overlapped with that of ir-NPY/DBH or ir-SP/CGRP fibers. We conclude that the NPY innervation of lymph nodes is sympathetic noradrenergic while nerves coding for co-existing SP and CGRP are most likely of sensory origin. The nerves containing co-existing VIP and PHI may be of heterogenous origin (sensory, cholinergic sympathetic, and/or parasympathetic). We suggest that these distinct sensory and autonomic peptidergic pathways linking the nervous system with the lymph nodes may play a differential role in bidirectional neuroimmunomodulation.

Adrenergic Fibers↗

The role of brain peptides in neuroimmunomodulation.

Since neuroimmunomodulation is brought about in part, at least, by secretion of pituitary hormones involved in stress and immune responses, we review briefly the hypothalamic control of the release of ACTH, growth hormone, and prolactin. The release of ACTH is controlled particularly by corticotropin-releasing factor (CRF), but vasopressin has intrinsic releasing activity and potentiates the action of CRF at both hypothalamic and pituitary levels. Oxytocin may even potentiate the action of CRF, but has little, if any, ACTH-releasing activity by itself. In addition, epinephrine may augment responses to the CRFs. In contrast, growth hormone is under dual control by growth-hormone-releasing factor (GRF) and somatostatin, and prolactin is under multifactorial control by a series of inhibitors and stimulators. Dopamine is accepted as a physiological prolactin-inhibiting factor (PIF), but probably GABA and possibly acetylcholine as well are PIFs. There is good evidence for a peptide PIF as well. There are a number of prolactin-releasing factors (PRFs) which include oxytocin, vasoactive intestinal polypeptide, PHI and TRH. Several other peptides can also release prolactin, including angiotensin II. In response to stress there is a complex interaction of peptides intrahypothalamically. CRF augments its own release by an ultra short-loop positive feedback, and there is negative ultra short-loop feedback of GRF and somatostatin. Vasopressin appears to augment CRF release as well as to act directly on the pituitary, and there are complex interactions of various peptides to influence prolactin and GH release.

Adjuvants, Immunologic↗

Immunodeficient dwarfism in dogs: a model for neuroimmunomodulation.

This paper discusses the use of dogs as experimental models for neuroimmunomodulation and compares immunodeficient dwarfism in dogs to that in rodents. Immunodeficient dwarfism in dogs is reviewed including description of the clinical syndrome, immunologic characteristics, neuroendocrine abnormalities, thymus histopathology, and therapy.

Animals↗

Contemporary Topics in Neuroimmunomodulation.

The investigational subject of immunophysiology (neuroimmunomodulation, psychoneurophysiology) is known to be the studies of interactions between nervous and immune systems in normal and pathological conditions on different structural levels of interactions between these systems. It has been shown that expression of genes of immediate (c-fos) and rapid (IL-2) reactions in response to stimuli of non-immune nature occurs not only in lymphoid cells, but also in certain structures of central nervous system. In addition, there are many facts, demonstrating the elevation of IL-1 production by cells of monocyte-macrophage system and the expression of IL-1 genes in brain after action of irritants of different origin. The IL-1 level is revealed to be increased after action of different stress factors that can be predictable. The studies are started having concern with rather new and extremely important aspect of immunophysiology, that is the studies of cytokine expression in brain and its role in brain function. Now it is already clear that practically all the spectrum of cytokines is present in brain and many of them, including IL-1 and IL-2, are expressed not only on glial cells, but on neurons. Partly cytokine involvement is shown during the development of regulatory processes. For example, IL-1 and IL-2 stimulate production of corticotropin releasing and lutein stimulating factors. It is possible to suggest that this line of studies would be highly perspective either for immunology, or for physiology of XXI century.

Journal Article↗

Enkephalinase: a physiologic neuroimmunomodulator detected in the synovial fluid.

Enkephalinase (endopeptidase 24.11) is a metallopeptidase that is able to cleave not only neuropeptides and hormones but also immune mediators. The enzyme was quantified in synovial fluid obtained from 36 swollen joints. Its concentration correlated with the synovial fluid cell count, mainly the polymorphonuclear cells and lymphocytes, and with the erythrocyte sedimentation rate. No statistically significant difference in enkephalinase levels was demonstrated between the groups of patients with rheumatoid arthritis, seronegative spondylarthropathy, microcrystalline arthritis, or osteoarthritis. The presence of enkephalinase in the synovial fluid could reflect the intensity of the inflammatory process, or it could represent a physiologic regulator of inflammation and pain within the joint.

Arthritis↗

Close apposition of dynorphin-positive nerve fibres to lymphocytes in the liver suggests opioidergic neuroimmunomodulation.

The liver is innervated by sympathetic efferent, spinal afferent, vagal afferent and probably also vagal efferent fibres. To assess potential functional roles of the various neuronal subsets, data on transmitter systems are of crucial importance. This study was aimed at elucidating a possible opioidergic system in the mouse and rat liver. In particular relationships of opioidergic neurons to immune cells were emphasised. Material from perfusion-fixed mice ( n=29) of different strains (BALB/c, NMRI, C57Bl6, SV 129 inbred) and Wistar rats ( n=7) was cryosectioned at 12-14 microm and incubated for single or double immunofluorescence. Antibodies directed against dynorphin A, met-enkephalin, endomorphin 1 and 2, mu, kappa- and delta-opioid receptors (MOR, KOR, DOR), tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), CD4, CD8 and macrophages were used. Binding sites were detected using Cy3-, FITC-, DTAF-, Cy2-, Alexa 555- and Texas red-tagged secondary antibodies. Specimens were analysed using confocal laser scanning microscopy (CLSM). Numerous nerve fibres staining for dynorphin were found in periportal areas of both mouse and rat livers. Neither met-enkephalin nor endomorphin could be detected in axons. No immunopositive neuronal cell bodies or other cellular elements were seen. All dynorphin positive fibres costained for TH while not every TH-positive fibre costained for dynorphin. Thus, most if not all dynorphin-positive nerve fibres may be of sympathetic origin. KOR immunostaining could be localised to round mononuclear cells which often costained for CD4, less frequently for CD8 and rarely for the pan-macrophage marker BM8. Altogether, about 45% of KOR-positive cells were identified as T-lymphocytes. In some instances, close appositions of dynorphin-positive axons to KOR-positive cells were revealed by CLSM. No KOR immunoreactivity was detected in nerve fibres. Hence, sympathetic neurons innervating the liver may interfere with inflammatory processes, in addition to their well-established beta(2)-adrenergic effect, via an opioidergic action on immune cells.

Animals↗

Significance of initial emotional state for neuroimmunomodulation in conditions of activation and blockade of 5-HT(1A) receptors.

Experiments performed on male CBA mice immunized with sheep erythrocytes at a dose of 5 x 10(8) cells showed that the selective agonist of serotonin 5-HT(1A) receptors 8-OH-DPAT (1 mg/kg) suppresses the immune response in aggressive animals. In mice demonstrating the submissive type of behavior, formed during 10 days of experience of defeats, activation of 5-HT(1A) receptors with 8-OH-DPAT had no effect on the immune response. However, treatment with the selective 5-HT(1A) receptor blocker WAY-100635 stimulated the immune response, but only in submissive mice. These data lead to the conclusion that activation and blockade of 5-HT(1A) receptors have different effects on the immune response in CBA mice depending on the initial emotional state of the animals, due to different activities of neurotransmitter systems, particularly the serotoninergic, in aggressive and submissive mice.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Stress-related neuroimmunomodulation of monocyte-macrophage functions in HIV-1 infection.

Monocytes/macrophages play a central role in the afferent and efferent limbs of the immune system. Macrophages perform several immunological functions both in vivo and in vitro, including antigen presentation, tumor cell killing, phagocytosis, and bacterial and viral killing. Acquired immunodeficiency syndrome (AIDS), a disease characterized by a profound immunodeficiency, induces a wide range of neuropsychological abnormalities. The occurrence of severe psychological disturbances, including stress, depression, and anxiety increase psychological and physical indices of morbidity among patients. Stress influences several immunological responses in man and animals and is usually accompanied by altered blood levels of various CNS-related peptides or neurohormones. Monocytes/macrophages express surface receptors for different CNS-secreted molecules. In ARC and AIDS patients abnormal neuropeptide levels may be related to severe psychological disturbances. Neuropeptides and neurohormones may play a central role in stressed HIV-1-infected patients by affecting monocyte-macrophage functions, which may further trigger disease progression and immunologic deficiency. It is hypothesized that stress reactions lead to altered release of neurohormones and/or neuropeptides which affect monocyte-macrophage functions and favor progression of HIV-1-related disease.

AIDS Dementia Complex↗