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Recent developments of Psychoneuroimmunology and Neuroimmunomodulation presented at the Second International Workshop on Neuroimmunomodulation (Dubrovnik 1-6 June 1986) are summarized. The bidirectional nature of the relationship between the central nervous system and the immune system is stressed.
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In 1987 in Dubrovnik, Yugoslavia, N.H. Spector named a new discipline: Neuroimmunomodulation. R. Ader called this new discipline psychoneuroimmunomodulation when the major emphysis was on its behavioral aspects. Neuroimmunomodulation (NIM) is devoted to the study of the interactions at different morphologic and functional levels among the immune, nervous, and endocrine systems. In fact, this science is the modern manifestation of an old science: in the words of B.D. Jankovic (1987), "Neuroimmunomodulation is a modern reflection in neurosciences and immunosciences of the ideas and experience of philosophers and ingenious observers of ancient Egypt, Greece, China, India, and other civilizations that the mind is involved in the defense against diseases." Twelve years ago NIM was regarded by many conventional scientists almost as a form of witchcraft. Today it may be the fastest growing area of biomedical science research in the world. Important clinical applications will not be far behind. NIM research has also progressed in the field of oncology research. Topics such as treatment of hormone-dependent cancer with analogues of hypothalamic hormones, the role of opioids and T cells in cancer, stress-cancer-immune connections, the anticancer role of melatonin and cytokines, immunotherapy of cancer, and the role of psychotherapy in cancer patients represent some lines of research that have been or are being investigated by scientists. Some areas remain to be thoroughly investigated such as the influence of physical exercise (sports), music (classical or modern), and/or relaxation techniques (e.g. yoga) on the development of human cancer. This paper reviews the role of NIM in oncology and provides some perspectives for further research and development of clinical applications.
A major system of neuroimmunomodulation is the hypothalamic-pituitary-adrenocortical (HPA) axis, acting through glucocorticoids and their intracellular signaling components, exerting both stimulatory and inhibitory effects on the immune reaction. Glucocorticoids inhibit the production of proinflammatory cytokines by interacting with nuclear transcription factors (nuclear factor [NF]-kappaB, activated protein [AP]-1) and induce the production of several anti-inflammatory cytokines by gene activation. In some cells and/or in extreme stress conditions, apoptosis is evoked. In most processes related to neuroimmunomodulation a prominent role is emerging for mitochondria. These organelles generate more than 90% of the cell's energy requirements through oxidative phosphorylation (OXPHOS), which is regulated by several agents, including steroid and thyroid hormones. These hormones are inducers of nuclear and mitochondrial OXPHOS gene transcription and they exert a primary action not only on nuclear but also on mitochondrial genes by way of cognate receptors. Recently, additional nuclear transcription factors involved in neuroimmunomodulation have been detected in mitochondria (NF-kappaB, AP-1, p53, calcium/cAMP response element binding protein [CREB]), and binding sites of these and putative binding sites of other nuclear transcription factors have been identified in the mitochondrial genome. The interaction of these factors with mitochondrial regulatory proteins, with receptors and with the genome has been shown and, in some cases, modulation of mitochondrial transcription was observed with possible effects on energy yield. The mitochondria store a host of critical apoptotic activators and inhibitors in their intermembrane space and the release of these factors could be another possible mode of action of the mitochondrially translocated regulatory agents and receptors.
Wistar strain male albino rats lesioned and sham lesioned at Ventromedial hypothalamus (VMH) were used to study the neuroimmunomodulation by this brain region. Except the decrease in thymus weight/body weight ratio (P < 0.01), and its cellularity (P < 0.02) in immunized VMH lesion animals, the rest of the parameters like plaque forming cells (PFC), antibody titre, leukocyte migration inhibition index, foot pad thickness in the lesioned as well as the lesion immunized animals never deviated from their respective sham and immunized sham animals. Sham operated belongs to VMH when compared to control rats, showed marked decrease in spleen weight (P < 0.001), thymus weight (P < 0.02) and decrease in popliteal lymph node weight (P < 0.001) ratios. After immunization, the immunized sham animals showed a marked decrease in antibody titre (P < 0.05), PFC (P < 0.05), spleen (P < 0.05) and thymus (P < 0.001) weight ratios with the significant increase in splenic cell count (P < 0.01) compared to immunized control rats. VMH may be one of the information receiving center. However, from these results, it is inferred that VMH could not be a modulating center for the many of the parameters studied as far as neuroimmunomodulation is concerned.
Modern scientific evidence of interactions among the nervous, endocrine, and immune systems dates from the late nineteenth century, although this concept was certainly known to the ancients in Asia, Europe, Africa, and the Americans. Within the past two decades, the mechanisms of these interactions, known today as neuroimmunomodulation (NIM), have been investigated, from the subcellular to the behavioral levels, using the modern tools of receptor and membrane physiology, biochemistry, pharmacology, immunology, chronobiology, and genetics. One of the best demonstrations of neural-immune interactions was classical (Pavlovian) conditioning of immune responses, first reported by Metal'nikov et al. at the Pasteur Institute in the 1920's. Within the past 10 years, my colleagues at the University of Alabama in Birmingham and the Gerontology Research Center in Italy, and I, in experiments with mice, demonstrated (a) a 3- to 39-fold enhancement of natural killer (NK) cell activity by conditioning; (b) reversal of an otherwise fatal cancer (myelo-MOPC-104 E) by perinoculation conditioning ; and (c) that very old animals can be similarly conditioned to increase, many fold, their NK activity in the absence of an antigen. NK cells are among the body's first-line defenses against cancer and viral infections. Research on NIM and its mechanisms is growing exponentially; indeed, it may be the fastest growing field in biomedical sciences. (The International Society for NIM, founded only a few years ago, now has active members in 40 countries.) This revolution in the basic sciences will undoubtedly lead to a corresponding revolution in clinical practice and, most importantly, in the area of preventive medicine.
OBJECTIVE: A predominance of sensory neuropathy was earlier described in Sjögren's syndrome (SS), which might precede the presence of sicca symptoms. The mechanism of sensory neuropathy in SS is unknown. Therefore, the aim of this study was to determine the quantitative changes of the different neuropeptide containing nerve terminals and the immunocompetent cells in labial salivary glands of primary SS. DESIGN: Immunohisto- and immunocytochemical methods were used for the detection of immunoreactive (IR) elements and the data were compared with the healthy controls. RESULTS: All of the investigated IR nerve fibres were found in different quantity and localisation in both of control and SS glands. The density of them was changed variously in SS. The number of the substance P (SP), neuropeptide Y (NPY) (P < 0.05), galanin (GAL) IR nerve terminals was decreased, however, the number of vasoactive intestinal polypeptide (VIP) and tyrosine beta-hydroxylase (TH) IR nerve fibres (P < 0.05) was increased compared to the control. There were no IR immunocompetent cells in the control materials, however, a large number of them showed IR for SP (46.2%) and NPY (34.4%) in the SS. The IR was demonstrated mainly in the mast cells, plasma cells and some of the lymphocytes. CONCLUSIONS: These neuropeptides might have a role in the sensory neuropathy; they might activate nociceptive and sympathetic pathways. Some neuropeptides (SP, NPY) are endogenous in the immune system and produced in certain conditions, e.g. inflammation and chronic autoimmune disorders such as SS, so they might participate in the neuroimmunomodulation and contribute to the atrophy, apoptosis and necrosis.
The current understanding of the pathophysiology of atherosclerosis leading to coronary artery disease (CAD) emphasizes the role of inflammatory mediators. Given the bidirectional communication between the immune and central nervous systems, an important question is whether the brain can be "informed" about and modulate CAD-related inflammation. A candidate communicator and modulator is the vagus nerve. Until now, the vagus nerve has received attention in cardiology mainly due to its role in the parasympathetic cardiovascular response. However, the vagus nerve can also "inform" the brain about peripheral inflammation since its paraganglia have receptors for interleukin-1. Furthermore, its efferent branch has a local anti-inflammatory effect. These effects have not been considered in research on the vagus nerve in CAD or in vagus nerve stimulation trials in CAD. In addition, various behavioural interventions, including relaxation, may influence CAD prognosis by affecting vagal activity. Based on this converging evidence, we propose a neuroimmunomodulation approach to atherogenesis. In this model, the vagus nerve "informs" the brain about CAD-related cytokines; in turn, activation of the vagus (via vagus nerve stimulation, vagomimetic drugs or relaxation) induces an anti-inflammatory response that can slow down the chronic process of atherogenesis.
The aim of the present study was to test the possibility that the catecholaminergic projectional pathway from the vagus nerve to the medullary visceral zone (MVZ) thence to the paraventricular nucleus of hypothalamus (PVN) was involved in the cytokine-to-brain communication. A triple labeling method in which WGA-HRP retrograde tracing was combined with anti-Fos and -TH immunohistochemical staining was used. WGA-HRP was stereotaxically injected into unilateral PVN in the rat, after a survival of 48 h, animals received intraperitoneal injection of lipopolysaccharide (LPS). The distribution of the HRP retrogradely labeled neurons, Fos protein positive and catecholaminergic neurons (tyrosine hydroxylase as marker) in the MVZ was observed. Subdiaphragmatic vagotomy (SDV) and sham surgery were also used to observe the different Fos expression in the MVZ after intraperitoneal administration of lipopolysaccharide (LPS) or pyrogen-free saline (NS). Under light microscope, seven types of positively stained neurons could be distinguished within the MVZ, namely neurons single-labeled with Fos, HRP or TH, respectively; neurons double-labeled with Fos/TH, Fos/HRP or HRP/TH separately; and neurons triple-labeled with Fos, HRP and TH staining. Intraperitoneal LPS caused lots of robust Fos expression within the MVZ in the sham surgery groups and this response in the MVZ was markedly inhibited in the vagotomized rats. The results suggested that some catecholaminergic neurons in the MVZ could send projections to the PVN and this pathway might be involved in the relay of peripheral immune information via vagus nerve. MVZ was a neural relay station in the immune-to-brain communication and might play a significant role in the neuroimmunomodulation via vagus-MVZ-PVN pathway.
During the last 20 years, mutual communications between the immune, the endocrine and the nervous systems have been defined on the basis of physiological, cellular, and molecular data. Nevertheless, a major problem in the new discipline "Psychoneuroimmunology" is that controversial data and differences in the interpretation of the results make it difficult to obtain a comprehensive overview of the implications of immunoneuroendocrine interactions in the maintenance of physiological homeostasis, as well as in the initiation and the course of pathological conditions within these systems. In this article, we will first discuss the afferent pathways by which immune cells may affect CNS functions and, conversely, how neural tissues can influence the peripheral immune response. We will then review recent data, which emphasize the (patho)physiological roles of hippocampal-amygdala structures and the nucleus accumbens in neuroimmunomodulation. Neuronal activity within the hippocampal formation, the amygdaloid body, and the ventral parts of the basal ganglia has been examined most thoroughly in studies on neuroendocrine, autonomic and cognitive functions, or at the level of emotional and psychomotor behaviors. The interplay of these limbic structures with components of the immune system and vice versa, however, is still less defined. We will attempt to review and discuss this area of research taking into account recent evidences for neuroendocrine immunoregulation via limbic neuronal systems, as well as the influence of cytokines on synaptic transmission, neuronal growth and survival in these brain regions. Finally, the role of limbic structures in stress responses and conditioning of immune reactivity will be commented. Based on these data, we propose new directions of future research.
Compelling evidence is presented to support the hypothesis that psychological processes affect immune function. Consequently, it is argued that psychological processes should be included in human immunological studies and that neuroimmunomodulation could accurately by called psychoneuroimmunology.
Recent research indicates that the proopiomelanocortin derivative alpha-melanocyte stimulating hormone (alpha-MSH) is a significant modulator of host reactions including fever and inflammation. Although the precise mechanism of action is still unknown, cytokine antagonism is believed to be responsible for at least a part of its anti-inflammatory/antipyretic influence: alpha-MSH antagonizes pyrogenic and proinflammatory effects of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and interferon gamma (IFN gamma). Although it is clear that the peptide can act within the brain to inhibit fever and peripheral inflammation, an anti-inflammatory effect on a peripheral target was evidenced in animals with transection of the spinal cord. Recent data show that alpha-MSH is significant also in human disorders such as AIDS, rheumatoid arthritis, and myocardial infarction. This molecule is believed to be a key factor in neuroimmunomodulation and it may be useful as a therapeutic agent in control of inflammatory reactions.
The microenvironments of the eye and brain are physiologically adapted to protect their delicate structures and functions from damaging immunogenic inflammation (delayed-type hypersensitivity). This adaptation is immune privilege. Aqueous humor, the fluid filling the ocular anterior chamber, suppresses antigen-stimulated primed T cells from mediating inflammation by inhibiting the production of the proinflammatory lymphokine interferon gamma. This suppression is mediated by immunosuppressive cytokines and neuropeptides constitutively produced in the eye and released into aqueous humor. Cerebrospinal fluid has similar immunosuppressive activities, cytokines, and neuropeptides as aqueous humor, indicating that similar mechanisms may mediate immune privilege in the eye and brain. The importance of neuropeptides in mediating immunosuppression indicates that immunosuppressive neuroimmunomodulation has a role in preventing induction of immunogenic inflammation within immune-privileged tissues.
This article reviews research on the role of psychological stress, personality, social support and other psychosocial factors in bacterial, viral and parasitic infections. After 100 years of research on man and animals, psychological stress is considered as a potential cofactor in the pathogenesis of infectious disease. Psychological stress seems able to alter the susceptibility of animals and man to infectious agents, influencing the onset, course and outcome of certain infectious pathologies. Many experiments have identified in neuroimmunomodulation the principal mediator of the alterations associated with conditions of stress. The development of psychoneuroimmunology has fostered in-depth study of the complex relationship between psychosocial factors, the central nervous system, the immune system and infectious disease. Although antimicrobial drugs have certainly remained the basis of all anti-infective therapy, this type of study has already led some authors to propose and experiment protocols of psychological intervention or psychoimmunotherapy in pathologies such as tuberculosis, or herpes simplex virus or human immunodeficiency virus infections. The psychoneuroimmunological approach to infectious diseases will probably grow in importance in the future not only in the setting of research in psychosomatic medicine but also in that of clinical microbiology.
Participation of a GABA-ergic system in neuroimmunomodulation was established through the use of a large number of chemical compounds which selectively modulate the activity of the GABA-BD-receptor-ionophore complex. Activation of the GABA-receptors with muscimol or activation of the BD-receptors with diazepam or tazepam had stimulatory effects upon immunogenesis. A decrease in the GABA-BD-receptor-ionophore complex activity led to a suppression of the immune response. The effect was achieved with: a blockade of the complex with bicuculline--a competitive inhibitor of the GABA-receptors: administration of a specific antagonist of the BD-receptors flumazenil or Ro 15-3505: or with blockade of chloride channels with picrotoxin. Activation of the GABA-ergic system causes an increase in bone marrow content of T-helper cells marked by L3T4. The immunomodulatory action of the GABA-ergic system is of central origin and can occur only when the hypothalamo-pituitary system is intact. Section of the pituitary stalk prevents accumulation of the T-helper cells in the bone marrow. The result show that the influence of GABA-ergic system on immunogenesis requires participation of both dopaminergic and serotoninergic systems.
Bilateral electrolytic destruction of the brain areas containing dopamine (DA) cell bodies (nuclei A9 and A10) as well as terminal regions of the nigrostriatal and mesolimbic DAergic systems (nuclei caudatus and accumbens) resulted in a considerable decrease in the intensity of the immune response in rats immunized with sheep red blood cells (SRBC). Administration of SRBC (5 x 10(8) i.p.) to rats produced a marked rise in activity of central DAergic system at early stage of the immune response formation. The most pronounced elevation in the concentration of DA and its metabolites, measured by the method of high performance liquid chromatography with electrochemical detection, was observed in the terminal regions of the nigrostriatal and mesolimbic DAergic systems (nuclei caudatus and accumbens), hypothalamus, hippocampus, amygdala within 20 min following antigen inoculation. By 60 min after immunization DA metabolism has been retained at a high level in all brain regions examined. The concentration of DA returned to control level in the amygdala and hypothalamus 24 hours after antigen administration and had a tendency to reach control values in the rest of the structures. The present results indicate that nigrostriatal and mesolimbic DAergic systems and DAergic structures of the hypothalamus are involved in the mechanisms of neuroimmunomodulation.