[Antiviral activity of immunomodulator Selank in experimental influenza infection].

The main objective of this study was to evaluate the antiviral properties of the glyproline Selank in both in vitro and in vivo against the influenza virus strain A/Aichi 2/68 (H3N2). The pronounced antiviral effect of the agent was detected in both systems. Selank added to the cell culture 24 hours before inoculation (a preventive use scheme) showed the highest efficiency, by completely suppressing viral reproduction. The in vivo studies also demonstrated that the highest survival of laboratory animals was observed when the agent was administered by the prevention scheme. The use of Selank in vivo induced the gene expression of interferon-alpha (IFN-alpha), without affecting that of interleukin (IL)-4, IL-10, or tumor necrosis factor-alpha (TNF-alpha). The findings suggest that the mechanism of the antiviral action of Selank may be due to its ability to modulate Th1/Th2/Treg cytokine equilibrium both directly and indirectly via the central nervous system. This is particularly promising if that the agent is synthesized on the basis of an endogenous peptide and that it has no negative effects is kept in mind.

[Neuroendocrine immunomodulation].

Close interaction between the immune and nervous systems is well documented. The ability of immunocompetent cells to express receptors to neuroendocrine mediators as well as secrete many of them is proved. The current literature suggests that the hormones of the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonodal axes play the most significant role in the regulation of immune responsiveness. On the other hand, the immune system communicates with the CNS directly through the cytokines that are able to cross the blood-brain barrier, or directly via the nervus vagus, as well as via secondary messengers. Receptors to a number of cytokines have been found in the nervous tissue. Moreover, glial cells are able to secrete cytokines in the amount significant enough for at least autocrine action. In this article, the authors review the role of the "major" stress hormones such as cortisol, DHEA, growth hormone in the regulation of immune response, as well as neuro- and psychotropic properties of two major groups of cytokines that support cell-mediated (Type 1) and humoral (Type 2) immune reactions. This review emphasizes neuro-endocrine-immune interactions in response to infection both under laboratory and clinical conditions.

[The endogenous regulation of the cytokine disbalance in humans subjected to simulated spaceflight environment].

Confinement is one of the stress-inducing factors which humans face in such terrestrial environments as those in polar winter-over expeditions, submarines, and is inevitable in space flights. Confinement regime (CR) itself includes a number of stress factors (e.g. psychological compatibility between crew members, microbiological contamination etc.), which have been shown to alter human immunity. Two groups of total seven subjects spent 110 days in closed-habitat chamber as part of SFINCSS (Stimulation of Flight of International Crew on Space Station) study. Distribution of T-cell subsets, NK-, B-cells, and monocytes in whole blood was assessed. Secretion of type I (IL-2, IFN-gamma, TNF-beta) and type II (IL-4, IL-10) cytokines in the LPS/PHA activated whole blood cell culture was assessed. Significant alterations in type I / type II cytokine equilibrium were observed during and after confinement. The data show that stress factors associated with confinement may lead to disbalance between cell-mediated and humoral immune reactions.

Immune responsiveness following academic stress in first-year medical students.

Many studies illustrate that physical or psychologic stressors can alter human immune function, which might predispose one to an increased susceptibility to infections. In the present study, we monitored immune responsiveness in 16 first-year medical students (age 23.8 +/- 2.2 years) during the first examination session. Baseline blood samples were collected 30 days prior to the first examination session. Subsequently, subjects were randomly assigned to two groups, and blood samples were collected at 24 h (POST24h) or 48 h (POST48h) after an examination. The percentage of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD3(+)CD45RO(+), CD3(+)CD45RA(+), CD3(-)CD16(+)56(+), CD19(+), and CD14(+) cells in whole blood was examined to determine changes in circulating immune cell populations. Activation of peripheral blood mononuclear cells (PBMC) with a mixture of phorbol myristate acetate (PMA) and ionomycin or lipopolysaccharide (LPS) for 4 h was used to assess the distribution of interleukin-2 (IL-2)-secreting or interferon-gamma (IFN-gamma)-secreting CD4(+) and CD8(+) cells, as well as IL-1alpha-secreting CD14(+) cells. Activation with a combination of phytohemagglutinin (PHA) and LPS was used to assess secretion of IL-2, IFN-gamma, IL-4, IL-10, soluble IL-2 receptor-alpha (sIL-2Ralpha), IL-1beta, and IL-1R antagonist (IL-1Ra) by PBMC in 48-h cell culture. A significantly higher level of total T cells was found at POST24h, and CD14(+) was elevated at both POST24h and POST48h. The percentage of CD4(+) and CD8(+) cells significantly declined at POST24 and POST48h. A significant elevation in the percentage of memory T cells was observed at POST48h, whereas the percentage of naive T cells was elevated at POST24h and POST48h. These changes were accompanied by a significant decline in percentage of natural killer (NK) cells 24 h after the examination. The percentage of IL-2-producing CD4(+) and CD8(+) cells was significantly lower at POST24h, and the percentage of CD8(+)IFN-gamma(+) cells significantly declined at POST48h. The percentage of CD14(+)IL-1alpha(+) significantly declined at both POST24 and POST48h. A significant decrease was observed in IL-2 secretion 24 h after the examinations, and the secretion of IL-4 and IL-1beta significantly declined at POST48h. No changes in IFN-gamma, IL-10, sIL-2Ralpha, and IL-1Ra secretion were observed. We conclude that the stress outcomes of academic examinations in first-year medical students can significantly alter immune cell distribution and in vitro production and secretion of specific cytokines.

Immunocompetent cells producing humoral mediators of bone tissue mineral metabolism during space flight simulation.

During 120-day and 370 day hypokinesia the possibility has been shown of manifestation of mechanism of immunological regulation of osteoclast functions. Supernatants of mononuclear peripheral blood cells which were in vitro nitrogen-stimulated, had an increased potential for resorption in 45Ca-labelled mice fetus long bone organ cultures. Resorbing activity was increased in mononuclear supernatants from some of the subjects exposed to 120-day hypokinesia and from all subjects exposed to 370-day hypokinesia. This variable returned to base-line values after completion of the bed-rest period. Lymphocyte in vitro proliferative activity decreased at the end of hypokinesia and during the initial days of recovery, and the number of active T-rosetting cells was, on the contrary increased. This suggested a possible activation of part of immunocompetent cell population potentially producing humoral regulators of bone cell functions in vivo. A study of a group of healthy males performing their routine daily activity and of patients with local osteoporosis (paradontitis) showed significant differences between normal subjects and patients, confirming the informative value of the method used and allowed to establish approximate limits of physiological variations of the values.

[Immunomodulatory effects of selank in patients with anxiety-asthenic disorders].

The purpose of this article was to study the immunotropic effects of the new neurotrophic heptapeptide selank. The experiments in vitro revealed that the drug in concentration 10-7 M completely suppressed gene expression by peripheral blood IL-6 of patients with depression but not of the healthy controls. At the same time, the significant increase (p<0,05) of IL-6 concentration was observed in the cell culture of peripheral blood of patients in the presence of selank. The changes of the Th1/Th2 cytokine balance in vivo were found in the serum of patients with generalized anxiety disorder and neurasthenia who received Selank during 14 days. The dynamics of these changes had the significant inverse correlation dependence. The cytokine regulating effects revealed in the study suggest that selank can be used as a novel immunomodulator in patients with anxiety-asthenic disorders. Additionally, the adaptogenic properties of selank may be beneficial to its use in elderly people and people exposed to environmental stressors for the prevention of infectious diseases.

[Immunologic mechanisms of regulating calcium metabolism in human bone tissue (production of osteoclast-activating factor) during long-term anti-orthostatic hypokinesia]. / Immunologicheskie mekhanizmy reguliatsii obmena kal'tsiia v kostnoi tkani cheloveka (produktsiia osteoklastaktiviruiushchego faktora) pri dlitel'noi antiortostaticheskoi gipokinezii.

During 370 days 10 healthy male subjects were exposed to antiorthostatic hypokinesia. The exposure enhanced the production of the osteoclast-activating factor (OAF) by blood mononuclear cells. The enhancement began after the 2nd month of hypokinesia and continued to increase thereafter. The index of resorption was: prior to hypokinesia--1.15 +/- 0.156, 8 months after onset--2.05 +/- 0.129, and 11.5 months after onset--2.37 +/- 0.296, the upper normal limit being 1.54. The changes were correlated with a greater amount of active T-lymphocytes in blood and a progressive increase of calcium negative balance. This investigation lends support to the previously formulated hypothesis (I. V. Konstantinova, 1986) that immunological mechanisms associated with the OAF production contribute to calcium metabolism disorders in human bone during prolonged space flights.

Effects of the 120 days of head-down bed rest on cytokine secretion and its in vitro modulation by glucocorticoids.

Antiorthostatic hypokinesia or head-down bed rest (HDBR), is a ground-based model system used to simulate some of the physioloical responses observed during space flight. Several studies involving humans and animals have demonstrated the effects of HDBR on different physioloical systems. HDBR produced a large thoracic fluid shift similar to that reported for space flight. Exposure to the combination of -6 degrees HDBR, emotional stress, and hypergravity led to an elevation of plasma histamine and serotinin and a dramatic decrease in the concentration of prostaglandins E, F2-alpha, and erthropoietin. These responses indicated the HDBR produces significant alterations in the neuroendocrine regulatory pathways. The proliferative response of immune cells in response to activators was significantly enhanced in antiorthostatically suspended mice; plasma corticosterone also was higher but splenic natural killer cell cytotoxicity remained unchanged after suspension. Bone-resporbing activity of supernatatants increased in mitogen-stimulated PBMC cultures of subjects exposed to -5 degrees HDBR for 370 days of HDBR. Proliferative activity of PBMCs had declined at the end of a 320-day HDBR and during the initial days of recovery, but the numbers of active rosette-forming T cells increased. These and other results suggest that most stress-induced immune changes are neuroendocrine modulated, and that corticosteroids play a significant role in this modulation. It is expected that HDBR-induced immune changes could result from similar mechanisms. In this study, we investigated the effect of 120 days of HDBR on Type-1 vs. Type-2 cytokine equilibrium in mitogen-activated PBMC culture, and how these reactions may correlate with changes in the neuroendocrine status.