[TOLL-LIKE RECEPTORS IN COSMONAUT'S PERIPHERAL BLOOD CELLS AFTER LONG-DURATION MISSIONS TO THE INTERNATIONAL SPACE STATION].

Studies of Toll-like receptors (TLR) in 20 cosmonauts-members of long-duration (124-199-day) missions to the International space station evidenced changes in relative and absolute counts of peripheral blood monocytes with TLR2, TLR4 and TLR6 on the surface, expression of TLR2 and TLR6 genes, and genes of molecules involved in the TLR signaling pathway and TLR-related NF-KB-, JNK/p38- and IRF pathways on the day of return to Earth. The observed changes displayed individual variability.

[Status of the osteoclast-activating system in cosmonauts after long-duration missions to the International Space Station].

The results of studying the system of osteoprotegerin/ receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) in 22 cosmonauts after long-duration (124 to 199 days) ISS missions are presented. Immediately on return to 1 g, changes were observed in OPG and RANKL serum levels and the ability to produce unstimulated and stimulated PGA of peripheral blood mononuclear cells in vitro. Individual variability of these changes was noticed. Our findings suggest that the cytokine OPG/RANKL-system is involved in bone remodeling in members of long-duration space missions.

[Immune system in Russian cosmonauts after orbital space flights].

The article is an overview of the results of studies of the immune systems of cosmonauts. The use of a system approach to the evaluation of the various components of the immune system made it possible to identify a number of characteristics of adaptive change, including the quantitative and functional changes of the innate and adaptive immunity. Among them the most important are: changes in in the system of Toll like receptors (TLRs) manifested as a decrease in the content of circulating monocytes and granulocytes expressing TLR2, TLR4, and TLR6, and LPS-induced cytokine production; inhibition of the functional potential of natural killer (NK)- and T-cells. The article discusses possible factors and mechanisms of the identified changes.

[Immunological aspects of a piloted mission to Mars].

The paper deals with the results of the effects of 520-day isolation and confinement modeling some elements of a mission to Mars on the immune system. Longitudinal analyses revealed that the mechanisms of adaptive response of the human immune system to the conditions of extremely long isolation led to a change of the parameters, characterizing innate and adaptive immunity. Among them the most important are: changes in the signaling PRRs--TLR, manifested in the reduction of the percentage of circulating monocytes and granulocytes expressed on its own surfaces TLR2, TLR4 and TLR6, decreases early NK cell activation potential, increases in the percentage T- and B-lymphocytes, that expressed early activation marker CD69 after adequate stimulation, and in production of cytokines in response to PHA stimulation. The active mobilization of the mechanisms of adaptive immunity, the implementation of the function of the level of immunity to a qualitatively different level, apparently, should be taken as a sign of adaptive adjustment of an organism in response to the complex influence of unfavorable factors, aimed at the preservation of immune homeostasis.

The impact of short-term confinement on human innate immunity.

During space missions cosmonauts are exposed to a myriad of distinct stressors such as radiation, overloads, weightlessness, radiation, isolation in artificial environmental conditions, which causes changes in immune system. During space flights it is very difficult to determine the particular factor associated with the observed immunological responses. This makes ground-based experiments examining the effect of each space flight associated factor along of particular value. Determining mechanisms causing alterations in cosmonauts' immunity can lead to potential targets for different countermeasures. In the current article we present the study of the early period of adaptation of human innate immunity of 6 healthy test-subjects, 4 males and 2 females aged 25 through 40, to isolation factors (hypodynamia, psychological stress, artificial environment). We measured multiple parameters characterizing innate immunity status in blood samples at chosen time points before, during and after the mission. In the experiment, highly enhanced cytokine responses were observed upon ex vivo antigen stimulations in comparison to baseline values. For cellular parameters we found multidirectional dynamics with a persistent prevalence of increasing TLRs+ monocytes as well as TLRs expression. Our study provides evidence that even a short-term confinement leads to immune changes in healthy humans that may trigger aberrant immune response.

Endothelial dysfunction markers and immune response indices in cosmonauts' blood after long-duration space flights.

Space flight factors are known to cause a malfunction in the human immune system and lead to damage to blood vessels. The hemostatic function of endothelium during space missions and its interaction with human immunity has not been determined so far. In this work, we investigated the markers of endothelial activation and damage (plasma concentrations of soluble thrombomodulin fraction (sTM), von Willebrand factor (vWF), highly sensitive C-reactive protein (hs-CRP)), as well as the level of D-dimer and compared them to the immunological parameters characterizing the state of human humoral and cellular immunity. The immune status of long-duration ISS crewmembers was assessed by whole-blood testing, and comprehensive postflight immune assessment included the analysis of leukocyte distribution. Flow cytometry was applied to determine the absolute counts and the percentage of lymphocyte subsets: B cells (CD19+), T cells (CD3+, CD3+CD4+, CD3+CD8+), NK cells (CD3-CD16+CD56+, CD11b+CD56+), and activated subsets (CD3+CD25+ and CD3+HLA-DR+). The in vitro basal cytokine production was investigated in whole blood cell culture. The cytokines IFN-gamma, IL-1-beta, IL-4, IL-6, IL-10, IL-18, and TNF-alpha were measured in plasma and the 24-h supernatants by a sensitive enzyme-linked immunosorbent assay. A significant increase in the plasma levels of vWF and hs-CRP and a decrease in the concentration of sTM after spaceflights were detected. Divergent changes in the parameters characterizing the state of the immune system were observed. We propose that the changes revealed may lead to an increase in the procoagulant activity of blood plasma, suppression of protein C activation and thrombin inhibition, as well as to an increase in the adhesive-aggregate potential of platelets, especially in case of changes in the rheological characteristics of blood flow during re-adaptation to ground conditions. We also speculate that the immune system might play an important role in vessel damage during long-duration missions.

[Dynamics of blood concentration of neurospecific proteins and risk of neuropathy development in the conditions of 105-day confinement].

Six male volunteers (aged 25 to 40 years) were subjects in all-round psychophysiological, hormonal and immunological studies before, in and after 105-day isolation and confinement. Blood was drawn and the 16-factorial Cattell personality inventory was filled out every 30 days. Concentrations of blood hormones, neurospecific proteins and cytokines point to a close interrelation between antibody titers to myelin-associated glycoprotein and changes in the parameters of metabolism and reproduction-related hormones, as well as cytokines and individual psychophysiology (extra-introversion, dominance, intropunitiveness, social contact selectivity, etc.), and suggest a minimum risk of demyelinizing neuropathy due to exposure to the conditions of isolation and confinement.

[Congenital human immunity during 5-day dry immersion].

The system of congenital immunity was studied in 12 essentially healthy males 18 to 26 years of age subjected to 5-day dry immersion without use of countermeasures. Peripheral blood was analyzed for monocytes, granulocytes and lymphocytes expressing the TLR2+, TLR4+, TLR6+, CD11b+, CD14+, CD16+, CD18+, CD24+, CD36+, CD54+, CD56+ and CD206+ receptors. Expression of early activation marker CD69 on lymphocytes-natural killers was studied in unstimulated and interleukin-2 activated mononuclear cell cultures. The negative shifts in the congenital immunity system in some volunteers at the end of immersion and during recovery can be considered as warnings about depletion of the system reserve and increase of the risk of infectious diseases such as caused by normal microflora which typically does not provoke pathological reactions of the host.

[Analysis of the relationships between the psychophysiological status and system of adaptive immunity in the conditions of 5-day dry immersion].

Relationships of the T- and B-components of adaptive immunity and the psychophysiological status were studied in 14 volunteers for the experiment with 5-d dry immersion (DI) w/o countermeasures. Comparison of frequency of deviations in immunity parameters of psychologically different subjects demonstrated the highest frequency in non-anxious and extravert individuals on day-5 in DI. These differences in immune reactions as a function of psychological type and temperament point to existence of a neuroimmune typology and, therefore, the necessity of concurrent immunologic and psychological investigations in order to develop separate measures of rehabilitation from and prevention of stress in people with polar psychological status.

[Indicators of innate and adaptive immunity of cosmonauts after long-term space flight to international space station].

Results of innate and adaptive immunity indicators research at 12 cosmonauts who took part in long (128-215 days) expeditions to the International space station (ISS) are presented. It is shown that a space flight can lead to deflection of deviations in human immune system. These shifts occurred in decrease of phagocytes, NK, T-lymphocytes functional activity and also in abilities of immunocompetent cells to synthesize cytokines. Significant individual changes are noted in reaction of immune system to the long term space flight conditions specifying on individual predisposition to development of immune reactance infringements in the conditions of varying gravitational influences.

[Human immunity system status during 7-day dry immersion].

Subpopulations of lymphocytes, activation potential of T-, B- and NK-cells as well as cytokines production by immunocompetent cells in peripheral blood were studied in five volunteers for 7-day dry immersion without use of countermeasures. Results of the investigation revealed several negative shifts in the immunity and cytokines systems instigated by the experimental conditions. The considerable variability of the immune reactions to immersion suggests individual predisposition to immunological breaks in a changed gravity environment.

[Immune system parameters of healthy humans in a chamber experiment with hyperbaric oxygen-nitrogen-argon air].

The investigation into the immune effects of 9-d exposure to elevated pressures of normoxic and hypoxic O2-N-Ar atmosphere showed changes in a number of indices of genetic and adaptive immunity in normal humans. Dynamics and depth of the functional shifts under the influence of the experimental factors appear to be connected with genetically coded mechanisms of immunoreactivity. Monitoring of immune homeostasis is basic to the prevention of immune adaptation failure.

[Immunoglobulin e and allergen-specific IgE antibodies in cosmonauts before and after long-duration missions on the International Space Station].

Immunoglobulins (IgG, IgA, IgM, IgE), specific IgE-antibodies, and interleukin-4 (IL-4) were investigated in blood serum of nine cosmonauts before and after 128- to 195-day ISS missions. It was shown that long-duration space flight does not change significantly the content of serum immunoglobulins, allergen-specific IgE-antibodies or IL-4. Analysis for probable ratios of the total IgE and IL-4 contents in the pre- and post-flight periods did not reveal any linear correlation of these parameters.

Immune changes during long-duration missions.

Immune changes during space flights in excess of two weeks have been almost exclusively studied by Russian investigators. Most of these studies have compared postflight values with those obtained before flight. In a very few cases, analyses have also been attempted during flight or with samples collected during flight. Studies of cosmonauts during spaceflight have shown that IgG levels were unchanged, whereas IgA and IgM levels were sometimes increased. Additionally, inflight delayed type hypersensitivity testing demonstrated a decrease below the warning level in 1/3 of the cosmonauts tested. Pre- vs. postflight analyses have often revealed a postflight decrease in: PHA-triggered lymphocyte blast transformation; the proliferation index of T-lymphocytes in the xenogeneic graft versus host reaction; the mitogen-induced production of interleukin-2; the presence of certain leukocyte sub sets; and cytotoxic activity of natural killer cells. Other factors that either did not change, or changed in an apparently random manner after flight included: production of alpha and gamma interferon; autoimmune tests; and globulin classes.

Immune changes in test animals during spaceflight.

Over the past two decades, it has become apparent that changes in immune parameters occur in cosmonauts and astronauts after spaceflight. Therefore, interest has been generated in the use of animal surrogates to better understand the nature and extent of these changes, the mechanism of these changes, and to allow the possible development of countermeasures. Among the changes noted in animals after spaceflight are alterations in lymphocytic blastogenesis, cytokine function, natural killer cell activity, and colony-stimulating factors. The nature and significance of spaceflight-induced changes in immune responses will be the focus of this review.

[Modification of a method for determining the cytotoxic activity of lymphocytes--natural killers in space experiments].

A space modification of a method for determining the cytotoxic activity of natural killers (NK) uses cultures of human lymphocytes and re-inoculated suspension of tumorous myeloblasts K-562. The 3H-uridine labeled target-cells fixated in 0.1 % formalin solution proved to be best suited to the conditions prohibiting regular recharge of cultural medium and utilization of radioactive agents. The following practical conclusions were made from the space-flown experiment: pre-launch procedures (lymphocyte isolation and delivery to the launch site) and time period till dock must not be longer than 5 days (1) and during transportation to the orbiting vehicle cell cultures must be kept at 18-20 degrees C (2). The modified method can be employed to study various aspects of cell interaction such as the NK ability to destroy target-cells in suspension cultured exposed in microgravity.

Effect of spaceflight on natural killer cell activity.

The effects of spaceflight on immune cell function were determined in rats flown on COSMOS 2044. Control groups included vivarium, synchronous, and antiorthostatically suspended rats. The ability of natural killer cells to lyse two different target cell lines was determined. Spleen and bone marrow cells obtained from flight rats showed significantly inhibited cytotoxicity for YAC-1 target cells compared with cells from synchronous control rats. This could have been due to exposure of the rats to microgravity. Antiorthostatic suspension did not affect the level of cytotoxicity from spleen cells of suspended rats for YAC-1 cells. On the other hand, cells from rats flown in space showed no significant differences from vivarium and synchronous control rats in cytotoxicity for K-562 target cells. Binding of natural killer cells to K-562 target cells was unaffected by spaceflight. Antiorthostatic suspension resulted in higher levels of cytotoxicity from spleen cells for 51Cr-labeled K-562 cells. The results indicate differential effects of spaceflight on function of natural killer cells. This shows that spaceflight has selective effects on the immune response.

[Tuberculin-dependent and nonspecific migration activity of leukocytes in astronauts]. / Tuberkulinzavisimaia i nespetsificheskaia migratsionnaia aktivnost' leikotsitov u kosmonavtov.

There have been presented the results of studying the reactivity of leucocytes with respect to tuberculin and monspecific migration activity of leukocytes in the cosmonatus pre flight and after completion of orbital expeditions of various duration are presented. In some cosmonauts tuberculin rearranged migration of leukocytes. This may bear witness to activisation of the immunity system in response to the antigens which had been already familiar to test-subjects. Experimental data pointed to significant changes in leukocyte mobility in 12 out of 28 cosmonauts examined on days 1 and 7-14 of recovery after the first or repeated long-duration space missions indicating some functional disorders in the phagocytic link which may lead to a typical decline in human resistance to infections.

[Migration capacity of phagocytes during simulation of some spaceflight factors under the terrestrial conditions]. / Migratsionnaia sposobnost' fagotsitiruiushchikh kletok pri modelirovanii faktorov kosmicheskogo poleta v nazemnykh usloviiakh.

Migration activity of the leukocytes featuring the functional state and metabolic activity of immunocompetent cells was studied. Migration of phagocyting cells was explored in 8 female test-subjects in the course of 120-day head-down bed rest and 3 male volunteers isolated in a hermetically sealed room over a similar period. Bed rest without use of preventive measures decreased significantly the migration activity of leukocytes; on the opposite, administration of the preventive measures by the bedrested subjects doubled the parameter. In the experiment with the long-term isolation the activity of leukocytes decreased significantly.

[Immunologic reactivity and status of the intestinal viral flora of humans in pressurized chambers]. / Immunologicheskaia reaktivnosti' i sostoianie kishechnoi virusnoi flory chekoveka pri obitanii v germetichno zamknutykh pomeshcheniiakh.

Immunity status and intestinal viral flora were studied in 5 experiments with long-term exposure of 26 male subjects in pressurized chamber. In two experiments with congenital microclimate and gaseous environment cellular and humoral indices of immunity did not deviate from the physiological norm. None of 14 subjects in these experiments was identified as a virus-carrier. In three experiments with hard environmental conditions (elevated concentrations of ammonia and carbon dioxide) viruses were isolated from 8 out of 12 subjects. Activation of viral flora mainly occurred on a background of impaired immunologic reactivity. In two experiments carriage of virus was asymptomatic; in the third experiment with the rise of ammonia up to 7 mg/m3 two subjects developed clinic signs that could have been engendered by enteric viruses, the Coxsackie B strain specifically.