Hugo Besedovsky - Academia.edu (original) (raw)

Papers by Hugo Besedovsky

European Journal of Immunology, May 1, 1977

The immune system is subject to an array of identified autoregulatory processes, but immunoregula... more The immune system is subject to an array of identified autoregulatory processes, but immunoregulation may also have a further basis in a network of immune‐neuroendocrine interactions. Two antigens each produced an increase of more than 100 % in electrical activity of individual neurones in the ventromedial but not in the anterior nucleus of the rat hypothalamus. Animals that failed to respond to antigen manifested no increase in the firing rate. These findings constitute the first evidence for a flow of information from the activated immune system to the hypothalamus, suggesting that the brain is involved in the immune response.

Periodicum Biologorum, Dec 1, 2004

Journal of Inflammation, Oct 29, 2016

Background: Neuroinflammation (NI) is a key feature in the pathogenesis and progression of infect... more Background: Neuroinflammation (NI) is a key feature in the pathogenesis and progression of infectious and non-infectious neuropathologies, and its amelioration usually improves the patient outcome. Peripheral inflammation may promote NI through microglia and astrocytes activation, an increased expression of inflammatory mediators and vascular permeability that may lead to neurodegeneration. Several antiinflammatory strategies have been proposed to control peripheral inflammation. Among them, electrical stimulation of the vagus nerve (VNS) recently emerged as an alternative to effectively attenuate peripheral inflammation in a variety of pathological conditions with few side effects. Considering that NI underlies several neurologic pathologies we explored herein the possibility that electrically VNS can also exert anti-inflammatory effects in the brain. Methods: NI was experimentally induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS) in C57BL/6 male mice; VNS with constant voltage (5 Hz, 0.75 mA, 2 ms) was applied for 30 s, 48 or 72 h after lipopolysaccharide injection. Twenty four hours later, pro-inflammatory cytokines (IL-1β, IL-6, TNFα) levels were measured by ELISA in brain and spleen extracts and total brain cells were isolated and microglia and macrophage proliferation and activation was assessed by flow cytometry. The level of ionized calcium binding adaptor molecule (Iba-1) and glial fibrillary acidic protein (GFAP) were estimated in whole brain extracts and in histologic slides by Western blot and immunohistochemistry, respectively. Results: VNS significantly reduced the central levels of pro-inflammatory cytokines and the percentage of microglia (CD11b/CD45 low) and macrophages (CD11b/CD45 high), 24 h after the electrical stimulus in LPS stimulated mice. A significantly reduced level of Iba-1 expression was also observed in whole brain extracts and in the hippocampus, suggesting a reduction in activated microglia. Conclusions: VNS is a feasible therapeutic tool to attenuate the NI reaction. Considering that NI accompanies different neuropathologies VNS is a relevant alternative to modulate NI, of particular interest for chronic neurological diseases.

Cellular Immunology, Sep 1, 1981

A postulated immunoregulatory role for the autonomous nervous system was explored utilizing sever... more A postulated immunoregulatory role for the autonomous nervous system was explored utilizing several in vivo and in vitro approaches. Local surgical denervation of the spleen in rats and general chemical sympathectomy by 6-hydroxydopamine combined with adrenalectomy yielded a ...

European Cytokine Network, Sep 1, 1998

Autonomic Neuroscience: Basic and Clinical, Aug 1, 2013

Brain Behavior and Immunity, Jul 1, 2022

The immune system, which evolved as a protective system, can paradoxically mediate lethal effects... more The immune system, which evolved as a protective system, can paradoxically mediate lethal effects when it is over-activated. These effects can be traced back to infected insects and are mainly mediated by phylogenetically old cytokines that have been found already in starfishes and sponges. We hypothesize that these anti-homeostatic effects are important for restricting the cumulative risk of transmission of highly mutating environmental pathogens that may endanger species, particularly when they start to originate and expand. Considering the Darwinian view that evolution is a permanent process, this anti-homeostatic program is preserved and expressed even when there is no risk for the species. Here, we review these aspects and discuss how evolutionary-imposed anti-homeostatic immune programs are expressed during acute and chronic human diseases, which can be further aggravated in the absence of medical interventions. The relevance of early identification of ancestral biomarkers that predict a shift from protective to deleterious immune outcomes is emphasized.

Journal of Neuroimmunology, 1991

We report the data concerning hae~atological and immunological changes observed in CPMS pts who u... more We report the data concerning hae~atological and immunological changes observed in CPMS pts who underwent LD-TE:] in a dollble blind, randomized clinical trial. Up to now ! 2 pts (9 female, 3 male;me.an age 42 yrs;mcan duration of the disease I I yrs) complated the 9th month follow-up. 7 pts tmder~vcnt LD-TBI (15 cGy at midplane, twice a week up to 150 cGy, using a 6 MeV photons) v/hi|e 5 pts underwent sham therapy. A l~ukopunia and an important lymphopenia was observed in all pts at the end of the LD-TI3! ~tment. We found a significative dec~ in all the peripheral blood mononuclear cell subsets (evaluated by monoclonal antibodies to leukocyte surface antigens) only in treated pts. At the 3rd month the CD3,CIM, and CD8 lymphocyte :mines r~mained significantly lower compared to basa! values (CD3 846"-152 vs 1338.-487 p<0.02; CD4 491±146 vs 946*_408 p<0.01, CD8 253*-99 vs 394+-204 p<0.02 cells/ram3) while the absolute value of the other subsets studied (CD25, Leu7, CD4Leu8) partially recovered. This trend was confirmed at 6th and 9th month after the end of LD-TBI (CD3 797-+136 and 866*-96; CD4 451-+42 and 472.-81; CD8 229._112 and 238+.106 cells/mm3 at 6th ~nd 9th month respectively). The mean CD4/CD8 ratio dropped at the first month follow-up (2.39-+0.77 vs 3.04-+1.81) and remained lower at the 3rd month evalw.tion (2.12+_1.24) with a subsequent progressive increase at the 9th month (2.67*_2.06).

Scandinavian Journal of Immunology, Aug 1, 2007

Tuberculosis (TB) may be regarded as a disease in which the immune response to Mycobacterium tube... more Tuberculosis (TB) may be regarded as a disease in which the immune response to Mycobacterium tuberculosis, its etiologic agent, is engaged both in protection and pathology. Different T‐lymphocyte subsets are involved in the immune response against M. tuberculosis, but production of interferon‐gamma (IFN‐γ) by T cells seems to be fundamental for disease control. Th1‐type cytokine responses predominate in patients with mild or moderate forms of pulmonary TB, whereas the production of Th2‐type cytokines prevails in the severe disease. Since the immune response fails to definitely eradicate the pathogen, a chronic infection is established, and it is likely that a broad range of regulatory mechanisms operate in this situation. Cytokines released during the course of an immune response activate the hypothalamus‐pituitary‐adrenal axis leading to the production of glucocorticoids and dehydroepiandrosterone (DHEA), with known immunomodulatory effects. TB patients exhibit increased concentrations of interleukin‐6 and cortisol in plasma, reduced DHEA and testosterone levels, together with remarkably increased growth hormone concentrations that were not accompanied by an expected raise in insulin‐like growth factor‐1. Significant increases in estradiol, prolactin, and thyroid hormone concentrations were also detected in patients. Cortisol inhibits the mycobacterial antigen‐driven proliferation and IFN‐γ production, whereas DHEA suppresses transforming growth factor beta production by lymphoid cells from TB patients with advanced disease. Furthermore, supernatants from cultures of M. tuberculosis‐stimulated mononuclear cells of TB patients inhibit DHEA secretion by a human adrenal cell line. This type of immuno‐endocrine interactions may affect the control of tissue damage and the development of protective immune responses, partly accounting for disease aggravation.

Journal of Pharmacology and Experimental Therapeutics, Jun 16, 2021

Neuroinflammation (NI) is an important physiologic process which promotes the tissue repair and h... more Neuroinflammation (NI) is an important physiologic process which promotes the tissue repair and homeostatic maintenance in the central nervous system after different types of insults. However, when it is exacerbated and sustained in time, NI plays a critical role in the pathogenesis of different neurologic diseases. The high systemic doses required for brain-specific targeting lead to severe undesirable effects. The intranasal (IN) route has been proposed as an alternative drug administration route for a better NI control. Herein, the brain biodistribution of intranasally administered dexamethasone versus intravenously administered one is reported. A higher amount of dexamethasone was found in every analyzed region of those brains of intranasally administered mice. HPLC analysis also revealed that IN administration allows Dex to arrive faster and in a greater concentration to the brain in comparison with intravenous administration, data confirmed by immunofluorescence and HPLC analysis. These data support the proposal of the IN administration of Dex as an alternative for a more efficient control of NI. SIGNIFICANCE STATEMENT This work highlights the biodistribution of dexamethasone after its intranasal administration. Intranasal administration allows for a faster arrival, better distribution, and a higher concentration of the drug within the brain compared to its intravenous administration. These results explain some of the evidence shown in a previous work in which dexamethasone controls neuroinflammation in a murine stroke model and can be used to propose alternative treatments for neuroinflammatory diseases.

International Journal of Tuberculosis and Lung Disease, Mar 1, 2018

(TB) is a major health problem worldwide. In TB, the immune and central nervous systems modulate ... more (TB) is a major health problem worldwide. In TB, the immune and central nervous systems modulate each other. The two main components of this network are the hypothalamicpituitary-adrenal axis (HPA) and autonomic nervous system (ANS).

Annals of the New York Academy of Sciences, Jul 1, 2012

Interactions between T cells and noradrenergic pathways were investigated using athymic nude mice... more Interactions between T cells and noradrenergic pathways were investigated using athymic nude mice as a model. Higher noradrenaline (NA) concentrations and increased density of noradrenergic fibers were found in the spleen and hypothalamus, but not in the kidney, of 21-day-old Foxn1 n (athymic) mice, compared with Foxn1 n /Foxn1 + (heterozygous) littermates. Although no differences in nerve growth factor concentrations were detected, significantly higher brain-derived neurotrophic factor concentrations were found in the spleen and hypothalamus of athymic mice compared with the controls. All of these alterations were abrogated in Foxn1 n mice reconstituted by thymus transplantation at birth. These results suggest that T lymphocytes or their products can induce (1) a decrease in the number and activity in splenic sympathetic nerve fibers; (2) a decrease in NA content in the hypothalamus, which, in turn, may influence the pituitary-adrenal axis and the descending neural pathways associated with the autonomic nervous system; and (3) changes in neurotrophin concentration in the spleen and hypothalamus.

Neurotherapeutics, Jul 6, 2020

Neuroinflammation triggered by the expression of damaged-associated molecular patterns released f... more Neuroinflammation triggered by the expression of damaged-associated molecular patterns released from dying cells plays a critical role in the pathogenesis of ischemic stroke. However, the benefits from the control of neuroinflammation in the clinical outcome have not been established. In this study, the effectiveness of intranasal, a highly efficient route to reach the central nervous system, and intraperitoneal dexamethasone administration in the treatment of neuroinflammation was evaluated in a 60min middle cerebral artery occlusion (MCAO) model in C57BL/6 male mice. We performed a side-by-side comparison using intranasal versus intraperitoneal dexamethasone, a timecourse including immediate (0 h) or 4 or 12 h poststroke intranasal administration, as well as 4 intranasal doses of dexamethasone beginning 12 h after the MCAO versus a single dose at 12 h to identify the most effective conditions to treat neuroinflammation in MCAO mice. The best results were obtained 12 h after MCAO and when mice received a single dose of dexamethasone (0.25 mg/kg) intranasally. This treatment significantly reduced mortality, neurological deficits, infarct volume size, blood-brain barrier permeability in the somatosensory cortex, inflammatory cell infiltration, and glial activation. Our results demonstrate that a single low dose of intranasal dexamethasone has neuroprotective therapeutic effects in the MCAO model, showing a better clinical outcome than the intraperitoneal administration. Based on these results, we propose a new therapeutic approach for the treatment of the damage process that accompanies ischemic stroke.

Journal of Neuropathology and Experimental Neurology, Dec 30, 2019

Relapsing-remitting multiple sclerosis, the most common form, is characterized by acute neuroinfl... more Relapsing-remitting multiple sclerosis, the most common form, is characterized by acute neuroinflammatory episodes. In addition to continuous disease-modifying therapy, these relapses require treatment to prevent lesion accumulation and progression of disability. Intravenous methylprednisolone (1-2 g for 3-5 days) is the standard treatment for relapses. However, this treatment is invasive, requires hospitalization, leads to substantial systemic exposure of glucocorticoids, and can only reach modest concentrations in the central nervous system (CNS). Intranasal delivery may represent an alternative to deliver relapse treatment directly to the CNS with higher concentrations and reducing side effects. Histopathological analysis revealed that intranasal administration of methylprednisolone to mice with experimental autoimmune encephalomyelitis (EAE) suppressed the neuroinflammatory peak, and reduced immune cell infiltration and demyelination in the CNS similarly to intravenous administration. Treatment also downregulated Iba1 and GFAP expression. A similar significant reduction of IL-1b, IL-6, IL-17, IFNc, and TNF-a levels in the spinal cord was attained in both intranasal and intravenously treated mice. No damage in the nasal cavity was found after intranasal administration. This study demonstrates that intranasal delivery of methylprednisolone is as efficient as the intravenous route to treat neuroinflammation in EAE.

Annals of the New York Academy of Sciences, Feb 1, 2009

Interleukin (IL)-1β induces a prolonged hypoglycemia in mice that is not caused by a reduction in... more Interleukin (IL)-1β induces a prolonged hypoglycemia in mice that is not caused by a reduction in food intake and is dissociable from insulin effects. There is a peripheral component in the hypoglycemia that the cytokine induces resulting from an increased glucose uptake, an effect that can be exerted in a paracrine fashion at the site where IL-1 is locally produced. However, the maintenance of hypoglycemia is controlled at brain levels because the blockade of IL-1 receptors in the central nervous system inhibits this effect to a large extent. Furthermore, there is evidence that the cytokine interferes with counter regulation to hypoglycemia. Here we report that administration of IL-1 or long-lasting insulin results in different changes in food intake and in neuroendocrine mechanisms 8 h following induction of the same degree of hypoglycemia (40-45% decrease in glucose blood levels). Insulin, but not IL-1, caused an increase in food intake and an endocrine response that tends to reestablish euglycemia. Conversely, a decrease in noradrenergic and an increase in serotonergic activity in the hypothalamus occur in parallel with a reduction of glucose blood levels only in IL-1-treated mice, effects that can contribute to the maintenance of hypoglycemia. These results are compatible with the proposal that IL-1 acting in the brain can reset glucose homeostasis at a lower level. The biologic significance of this effect is discussed.

International Journal of Cancer, Jun 15, 1988