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Hugo O Besedovsky

Publications and source records attributed to Hugo O Besedovsky.

14 recordsLinked to original sources
PubMed2007

Physiology of psychoneuroimmunology: a personal view.

This article offers a personal view on how the concept of the existence of a network of immune-neuro-endocrine interactions has evolved in the last 30 years. The main topic addressed is the relevance of the exchange of signals between the immune, endocrine and nervous systems for immunoregulation and brain functions. Particular emphasis is given to circuits involving immune cell products, the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. The operation of these circuits can affect immune functions and the course of inflammatory, autoimmune and infectious diseases. We also discuss increasing evidence that brain-born cytokines play an important role in brain physiology and in the integration of the immune-neuro-endocrine network.

Animals↗
PubMed2006

IL-1 resets glucose homeostasis at central levels.

Administration of IL-1beta results in a profound and long-lasting hypoglycemia. Here, we show that this effect can be elicited by endogenous IL-1 and is related to not only the capacity of the cytokine to increase glucose uptake in peripheral tissues but also to mechanisms integrated in the brain. We show that (i) blockade of IL-1 receptors in the brain partially counteracted IL-1-induced hypoglycemia; (ii) peripheral administration or induction of IL-1 production resulted in IL-1beta gene expression in the hypothalamus of normal and insulin-resistant, leptin receptor-deficient, diabetic db/db mice; (iii) IL-1-treated normal and db/db mice challenged with glucose did not return to their initial glucose levels but remained hypoglycemic for several hours. This effect was largely antagonized by blockade of IL-1 receptors in the brain; and (iv) when animals with an advanced Type II diabetes were treated with IL-1 and challenged with glucose, they died in hypoglycemia. However, when IL-1 receptors in the brains of these diabetic mice were blocked, they survived, and glucose blood levels approached those that these mice had before IL-1 administration. The prolonged hypoglycemic effect of IL-1 is insulin-independent and develops against increased levels of glucocorticoids, catecholamines, and glucagon. These findings, together with the present demonstration that this effect is integrated in the brain and is paralleled by IL-1beta expression in the hypothalamus, indicate that this cytokine can reset glucose homeostasis at central levels. Such reset, along with the peripheral actions of the cytokine, would favor glucose uptake by immune cells during inflammatory/immune processes.

Animals↗
PubMed2006

Expression of IL-1beta in supraspinal brain regions in rats with neuropathic pain.

We examined mRNA expression of the pro-inflammatory cytokine IL-1beta in the brainstem, thalamus, and prefrontal cortex in two rat models of neuropathic pain. Rats received a neuropathic injury: spared nerve injury (SNI) or chronic constriction injury (CCI), sham injury, or were minimally handled (control). Neuropathic pain-like behavior was monitored by tracking tactile thresholds. SNI-injured animals showed a robust decrease in tactile thresholds of the injured foot, while CCI-injured animals did not show tactile threshold changes. Ten or 24 days after nerve injury, IL-1beta gene expression in the brain was determined by RT-PCR. IL-1beta expression changes were observed mainly at 10 days after injury in the SNI animals, contralateral to the injury side, with increased expression in the brainstem and prefrontal cortex. The results indicate that neuro-immune activation in neuropathic pain conditions includes supraspinal brain regions, suggesting cytokine modulation of supraspinal circuitry of pain in neuropathic conditions.

Animals↗
PubMed2006

Endocrine and cytokine responses in humans with pulmonary tuberculosis.

Endocrine responses during chronic infections such as lung tuberculosis are poorly characterized. Hormonal changes are likely to occur since some of the cytokines produced during this disease could affect endocrine mechanisms that, in turn, influence the course of infectious/inflammatory processes. A main purpose of this work was to study endocrine responses involving pituitary, adrenal, gonadal, and thyroid hormones in parallel to IFN-gamma, IL-10, and IL-6 levels in tuberculosis patients with different degree of pulmonary involvement. We have also studied whether products derived from peripheral immune cells obtained from the patients can affect the in vitro production of adrenal steroids. The population studied comprised HIV-negative newly diagnosed, untreated male patients with mild, moderate, and advanced lung tuberculosis, and matched, healthy controls. IFN-gamma, IL-10, and IL-6 levels were elevated in patients with tuberculosis. Dehydroepiandrosterone and testosterone levels were profoundly decreased and growth hormone levels were markedly elevated in patients, in parallel to modest increases in cortisol, estradiol, prolactin, and thyroid hormone concentrations. Supernatants of peripheral blood mononuclear cells obtained from the patients and stimulated in vitro with Mycobacterium tuberculosis antigens significantly inhibited dehydroepiandrosterone secretion by the human adrenal cell line NCI-H295-R. These results support the hypothesis that at least some of the endocrine changes observed in the patients may be mediated by endogenous cytokines. The endocrine profile of tuberculosis patients would favor a reduction of protective cell-mediated immunity and an exacerbation of inflammation leading to perpetuation of the lung injury and to the hypercatabolic condition that characterizes this disease.

Adrenal Glands↗
PubMed2006

The role of noradrenergic nerves in the development of the lymphoproliferative disease in Fas-deficient, lpr/lpr mice.

Lpr/lpr mice develop a lymphoproliferative, autoimmune, lupus-like disease. These mice lack functional Fas (CD95) expression and are resistant to Fas ligand (CD178)-mediated apoptosis, a critical mechanism for the maintenance of peripheral tolerance. In this study, we show that noradrenaline (NA), the main sympathetic neurotransmitter, can induce apoptosis of lymphoid cells independently of functional Fas. Based on this finding, we used lpr/lpr mice as model to study the role of noradrenergic nerves in the expression of a lymphoproliferative disease. Early in ontogeny, the concentration of NA was significantly increased in the spleen of lpr/lpr mice, compared with normal littermates. However, splenic sympathetic innervation gradually declined as the disease progressed, and IgM blood levels and splenic NA concentration inversely correlated when the disease was overtly manifested. When the loss of noradrenergic fibers that occurred naturally during adult life in lpr/lpr mice was experimentally advanced by neonatal sympathectomy, the concentration of IgM and IgG2a in blood was markedly higher than that of control lpr/lpr mice, and the appearance of lymphadenopathy was accelerated. Furthermore, although neonatal denervation did not affect the life span of normal animals, it shortened significantly the survival time of lpr/lpr mice. These data show that, in addition to defects in the Fas pathway, an altered sympathetic innervation in lpr/lpr mice also contributes to the pathogenesis of the autoimmune disease, and strongly support the hypothesis that the sympathetic nervous system can modulate the expression of lymphoproliferative diseases.

Animals↗
PubMed2006

Murine taste-immune associative learning.

Taste-immune associative learning can result from contingent pairings of an immune-competent unconditioned stimulus (US) with a gustative conditioned stimulus (CS). Recalling such an association may induce a set of physiological responses affecting behavior, endocrine, and immune functions. We have established a model of behaviorally conditioned immunosuppression employing the immunosuppressant drug cyclosporine A (CsA) as the US and saccharin as the CS in rats and humans. In order to investigate the inter-species generalization of this neuro-immune interaction, we tested the feasibility of this paradigm in mice. In a single-bottle scheme, male BALB/c mice (n=5) were conditioned by conducting three association trials and a single recall trial. Control groups (n=5/group) were designed to assure associative learning, pharmacological effects of the US, and placebo effect. Results show that CsA-conditioned animals displayed significant immunosuppression in the spleen after recall, measured by in vitro T-lymphocyte proliferation, and IL-2 production. However, the same animals did not show evidence of avoidance behavior to the CS. In contrast, evoking the association of saccharin-lithium chloride (inducing gastric malaise) in another set of animals (n=4/group) resulted in significant and pronounced avoidance of the taste (CS). These animals also displayed significant suppression of splenic T-lymphocyte responsiveness after the recall phase. The present results indicate that mice seem to be capable of associating a gustative stimulus with CsA, resulting in behaviorally conditioned immunosuppression without affecting appetitive behavior.

Analysis of Variance↗
PubMed2006

Endogenous glucocorticoids cause thymus atrophy but are protective during acute Trypanosoma cruzi infection.

The cytokine-mediated stimulation of the hypothalamus-pituitary-adrenal (HPA) axis is relevant for survival during bacterial endotoxemia and certain viral infections. However, only limited information is available regarding the effects of endogenous glucocorticoids on parasite diseases. We have studied this issue using, as a model, C57Bl/6 and Balb/c mice infected with Trypanosoma cruzi, the causal agent of Chagas' disease. These two mouse strains differ in the susceptibility to infection with the parasite. An intense stimulation of the HPA-axis was observed 3 weeks after infection in both strains, but glucocorticoid levels were already increased two- to threefold in the less susceptible Balb/c strain during the first week. Blockade of glucocorticoid receptors with the glucocorticoid antagonist RU486, starting on day 10 after infection, partially reversed the thymic atrophy and decreased the number of CD4(+)CD8(+) thymocytes without affecting parasitemia and the number of inflammatory foci in the heart. However, tumor necrosis factor-alpha blood levels were increased in infected mice of both strains treated with RU486. Furthermore, the blockade of glucocorticoid receptors accelerated death in C57Bl/6J mice and increased lethality to 100% in Balb/c mice. The results obtained represent the first evidence that an endocrine host response that is coupled to the immune process can strongly affect the course of a parasite infection.

Adrenalectomy↗
PubMed2003

Central catecholamine depletion inhibits peripheral lymphocyte responsiveness in spleen and blood.

Experimental and clinical evidence has demonstrated extensive communication between the CNS and the immune system. To analyse the role of central catecholamines in modulating peripheral immune functions, we injected the neurotoxin 6-hydroxydopamine (6-OHDA) i.c.v. in rats. This treatment significantly reduced brain catecholamine content 2, 4 and 7 days after injection, and in the periphery splenic catecholamine levels were reduced 4 days after treatment. Central catecholamine depletion induced an inhibition of splenic and blood lymphocyte proliferation and splenic cytokine production and expression (interleukin-2 and interferon-gamma) 7 days after injection. In addition, central treatment with 6-OHDA reduced the percentage of spleen and peripheral blood natural killer (CD161 +) cells, and T-cytotoxic (CD8 +) cells in peripheral blood. The reduction in splenocyte proliferation was not associated with a glucocorticoid alteration but was completely abolished by prior peripheral sympathectomy. These data demonstrate a crucial role of central and peripheral catecholamines in modulating immune function.

Animals↗
PubMed2003

Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases.

The pathogenesis of chronic disabling inflammatory diseases (CDIDs) is poorly understood. Current concepts that focus on abnormalities of the immune system are, in our view, incomplete. Here we propose that chronic disruption of homeostasis through abnormal neuronal and endocrine host responses to transient inflammatory reactions contributes to the appearance of CDIDs. Coordinated reactions of the supersystems (immune, nervous, endocrine, and reproductive) that maintain homeostasis have been evolutionarily conserved to respond to and eliminate foreign agents over a period of days to a few weeks. If the responses of these supersystems fail to return to normal after elimination of the pathogen, a continuous aggressive immune response is created; this situation can trigger development of CDIDs. Maladaptation of the supersystems during CDIDs has not been evolutionarily conserved but is nevertheless still prevalent because a large proportion of these diseases tend to appear after the reproductive phase. We propose that this integrated systems hypothesis may permit better identification of a patient at risk or in the early stages of developing a CDID such as rheumatoid arthritis and enable more coordinated intervention than is presently attempted.

Adaptation, Physiological↗
PubMed2003

Sympathetic abnormalities during autoimmune processes: potential relevance of noradrenaline-induced apoptosis.

The sympathetic nervous system is one of the major pathways involved in immune-neuroendocrine interactions. Disturbances in these interactions are likely to have consequences during lymphoproliferative diseases. Work derived from our group as well as from several others led us to the hypothesis that the overstimulation of the immune system that characterizes this type of pathology results in decreased sympathetic nerve activity in lymphoid organs. To explore this possibility, we used as a model lpr/lpr mice, which develop a genetically determined autoimmune, lupus-like lymphoproliferative disease. We show that 18-week-old female C57Bl/6J lpr/lpr mice, which do not show overt symptoms of the disease but already have increased IgM and IgG2a levels in the blood, have decreased noradrenaline (NA) concentration and content in the spleen, but not in the kidney, as compared to normal C57Bl/6J littermates. Lpr/lpr mice do not express normal Fas, and therefore apoptosis cannot be triggered through this receptor. The defects in sympathetic innervation in the spleen of lpr/lpr mice prompted us to evaluate whether NA could influence lymphoid cell mass by inducing apoptosis. We found that NA can directly induce apoptosis in normal lymphoid cells via beta-adrenergic receptors. From the reported results we propose that reduction in sympathetic nerve function in lpr/lpr mice contributes to aggravation of the disease and suggest that in addition to the incapacity to mount Fas-mediated apoptosis, a second proapoptotic mechanism, namely, that triggered by NA, is defective in these animals because of reduced availability of the neurotransmitter.

Analysis of Variance↗
PubMed2002

Involvement of noradrenergic nerves in the activation and clonal deletion of T cells stimulated by superantigen in vivo.

Superantigens, like staphylococcal enterotoxin B (SEB), induce a strong proliferative response followed by clonal deletion of a substantial portion of defined Vbeta T cells. The remaining cells display in vitro anergy. We found that the immune response to SEB was paralleled by biphasic changes in the activity of the sympathetic nervous system. Furthermore, sympathetic denervation resulted in decreased SEB-induced cell proliferation and IL-2 production, and impeded the specific deletion of splenic CD4Vbeta8 cells observed in intact animals without affecting anergy. These studies provide the first evidence of an immunoregulatory cross-talk between sympathetic nerves and superantigen-activated immune cells.

Animals↗