Вы находитесь на странице: 1из 7

The immune system in space

and microgravity
GERALD SONNENFELD
Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA

ABSTRACT
SONNENFELD, G. The immune system in space and microgravity. Med. Sci. Sports Exerc., Vol. 34, No. 12, pp. 20212027, 2002.
Space flight and models that created conditions similar to those that occur during space flight have been shown to affect a variety of
immunological responses. These have primarily been cell-mediated immune responses including leukocyte proliferation, cytokine
production, and leukocyte subset distribution. The mechanisms and biomedical consequences of these changes remain to be established.
Among the possible causes of space flight-induced alterations in immune responses are exposure to microgravity, exposure to stress,
exposure to radiation, and many more as yet undetermined causes. This review chronicles the known effects of space flight on the
immune system and explores the possible role of stress in contributing to these changes. Key Words: EXTRATERRESTRIAL
CONDITIONS, RESISTANCE TO INFECTION, STRESS

T
he ability to visit space for longer periods of time has rameters do occur as a result of space flight. Several factors
opened up new aspects of research to determine the could contribute to those effects, including microgravity,
effects of space flight on numerous physiological stress, and radiation (17,40,58,65,77 80). It has been diffi-
functions. Among those being explored is the effects of cult to determine the relative contribution of each one of
space flight on the immune system (71). The purpose of this those factors to alterations in immunological parameters
review will be to explore the history of the study of the induced by space flight. Most importantly, although it is
effects of space flight on immunity. Because more oppor- clear that immune responses change, the possible effects of
tunities have existed to determine the effects of space flight space flight on actual resistance to infection have not been
on immune responses of animals, the main focus of the established.
review will be on animal models. Finally, a newly emerging Several studies in rats flown in space have indicated that
area of the interaction of the immune system with the prolonged space flight resulted in hypoplasia of lymphoid
neuroendocrine system during space flight will be explored. organs and alterations in mitogen-induced blastogenesis
(17,40). These effects were transient and returned to normal
after a postflight recovery period (17,40). Data obtained
SPACE FLIGHT AND IMMUNITY
from human studies showed that there was inhibition of
One of the important regulatory biology interactions af- mitogen-induced blastogenesis of lymphocytes obtained
fected by space flight is the regulation of the immune from astronauts and cosmonauts after the Apollo-Soyuz test
response. Alterations in the regulation of immunity could project, Skylab, Space Shuttle, and various Soviet flights
have profound effects on the ability of the host to resist (29,77 80). In these cases, the lymphocytes were obtained
infection and tumors. Reports on the effects of space flight from the crew after their return flight. Samples taken from
on the immune system have been interesting but not defin- the crews as late as 7 d postflight indicated that the blasto-
itive (17,40,58,65,77 80). These studies have been limited genic response had not returned to normal. The defects in
by the small sample size, the relatively small number of immune function may have been due to inhibition of mac-
flights available for immunological studies, and by experi- rophage function, but this has not been confirmed (78 80).
mental conditions (17,40,58,65,77 80). Nevertheless, it is Soviet/Hungarian studies have also indicated that some
now apparent that several alterations of immunological pa- cosmonauts had a severe decrease in the ability of their
leukocytes to produce interferon-/ (an important cytokine
Address for correspondence: Gerald Sonnenfeld, Ph.D., Department of that is both antiviral and immunoregulatory) when their
Microbiology, Biochemistry and Immunology, Morehouse School of Med- blood was sampled and tested immediately after return from
icine, 720 Westview Drive, S.W., Atlanta, GA 30310-1495; E-mail: flight (75). Fifteen of 29 Apollo crew members developed
sonneng@msm.edu. bacterial or viral infections during their missions or imme-
Submitted for publication February 2002. diately after return during the first week after recovery (24).
Accepted for publication June 2002.
The infectious agents included influenza viruses, Pseudo-
0195-9131/02/3412-2021/$3.00/0 monas aeruginosa, and -hemolytic streptococci (24). In
MEDICINE & SCIENCE IN SPORTS & EXERCISE the Apollo 13 mission, one crew member developed a uri-
Copyright 2002 by the American College of Sports Medicine nary tract infection with P. aeruginosa during the flight
DOI: 10.1249/01.MSS.0000039073.04569.B5 (76). It is possible that the changes in immune responses
2021
induced by space flight (changes in cytokine production tory results on the effects of space flight on the immune
capacity in particular) could have contributed to decreased system are due to the experimental conditions and parame-
resistance to infection. ters observed.
Human studies have indicated space-flightinduced Mice were maintained in a space cabin environment in
changes in human cell culture activities such a leukocyte which barometric pressure was altered (19). These confined
blastogenesis (3,1214) and signal transduction in leuko- mice were more susceptible to mengovirus infection than
cytes (34,56). Studies have also indicated that space flight were controls. These data suggested that maintenance of
alters leukocyte distribution (41,42,74), interferon and other mice in this restricted environment with alterations in pres-
cytokine production (16), and natural killer cell activity in sure could have resulted in alterations in immune responses
humans when measured after flight. Interferon-/ produc- that decreased their resistance to viral infections. By far, the
tion was found to be dramatically enhanced when cultures of most widely used model to simulate some aspects of weight-
leukocytes were flown and stimulated in space (75). Inter- lessness that occurs during space flight has been antiortho-
estingly, these were the cells from the same cosmonauts static (1520 head-down tilt), hypokinetic, hypodynamic
who were tested upon return to earth and shown to have suspension (no load on the hind limbs) (AOH). AOH sus-
inhibited interferon production (75). When assessed during pension has been carried out either by tail (26,46) or by
flight, delayed hypersensitivity responses to common recall harness (47), but immunological results have been similar
antigens are inhibited during both short-term (81) and long- using both forms of suspension. The suspension model
term (20) space flights. Models of space flight such as allows the development of physiological changes in muscle,
isolation and long-term bed rest with head-down tilt have bone, fluid shifts, and other parameters that are similar to
resulted in alterations of cytokine production and leukocyte some changes observed after weightlessness during space
function (55,57,67). As demonstrated with the interferon, flight (46,47). Rats suspended in this model have shown
some of these results have shown opposing results in dif- involution of the thymus similar to that seen after space
ferent flight experiments, i.e., in one experiment an immune flight (17,73). No effect of suspension of rats on levels of
parameter is decreased, and in another it is unaltered or immunoglobulin classes was observed (6), which is similar
increased. This is probably due to specific experimental to the lack of effect of space flight on levels of circulating
conditions, in vivo vs in vitro experiments, species of ex- immunoglobulin classes of astronauts (82). Therefore, de-
perimental subject, and complicating additional variables spite the obvious limitations of the model for simulating
that occur. Nevertheless, it is clear that exposure to space- some of the effects of weightlessness seen during space
flight conditions dramatically affects the immune system. A flight, it has been useful in aiding the determination of
recent study has shown that exposure of humans to sleep which immunological parameters should be studied in rare
deprivation, which can occur during space flight, results in flight experiments.
alterations of TNF- receptors and interleukin-6 levels in In our laboratory, we began our studies on the effects of
serum (61). space flight on immune responses by using the AOH sus-
Studies involving antibody responses have been much pension model. We utilized both the rat tail and harness
more limited. Short-term space flight has resulted in no suspension systems, and also developed a new mouse har-
change in total immunoglobulin levels (82), whereas long- ness suspension model (72). Suspension of mice in the new
term space flight has shown a small increase in total immu- model resulted in physiological changes that were similar to
noglobulin levels (29). Interestingly, a recent study has those observed using the rat suspension model (72). The
shown no effect of exposure on an Antarctic winter-over first series of experiments we carried out involved the study
model of isolation in the ability of human subjects to mount of cytokines. Cytokines are soluble, non-antibody mediators
an antibody response to bacteriophage X-174 (60). There- that play a major role in cell-to-cell communication and
fore, antibody responses may not be as sensitive to space regulation of immune responses (5). The first group of
flight or models of some components of space-flight con- cytokines we studied was the interferons. Interferons are a
ditions as are cell-mediated immune responses. family of proteins that have antiviral activity and several
As a result of the limited opportunities for space flight, other activities, including regulation of immune responses
animal models have been used to study changes in immune (5). Interferon- is produced primarily by leukocytes after
responses. Immune responses of rodents have been the main stimulation with viruses, double-stranded RNA, or other
subject of the studies. Cultures of rodent cells flown in space nonspecific inducers (5). Interferon- is produced primarily
have shown altered cytokine production (7) and macrophage by fibroblasts by the same stimuli as interferon- (5). In
hematopoiesis and function (2). Chapes and associates (8) many cases, they are difficult to separate and are referred to
found enhanced secretion of several cytokines, including commonly as interferon-/. The third type of interferon is
interferons- and -, interleukin-1, and tumor necrosis fac- interferon-. Interferon- is a product of an immune re-
tor-, after murine cells were cultured and challenged to sponse by T-lymphocytes stimulated either with specific
produce the cytokines during space flight. This is in accor- antigen or with a mitogen such as concanavalin-A or by
dance with results of Talas and associates (75), who found natural killer cells (5).
similar results using human cells. However, the ability of the The next studies performed by our laboratory showed that
tumor necrosis factor to kill cells was inhibited during space suspension of rats in an AOH model resulted in severe
flight (83). This again suggests that some of the contradic- inhibition of interferon-/ production (63). The rats were
2022 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org
suspended antiorthostatically in this tail suspension model orthostatically suspended mice became susceptible to infec-
for 2 wk and then challenged intravenously with polyriboi- tion, whereas orthostatically suspended mice remained re-
nosinic-polyribocytidylic acid (poly-I:C, a double-stranded sistant (22). Alterations in resistance to EMC-D virus
RNA inducer of interferon-/. There was an 80% decrease correlated with alterations in interferon production. There-
in interferon-/ production compared with normally caged fore, antiorthostatic suspension-induced changes in inter-
controls (63). In more recent studies, rats were suspended feron production could have contributed to the compro-
antiorthostatically for 12 wk, and spleens were removed mised resistance to EMC-D virus infection. This raises the
immediately after the rats were taken down from suspen- possibility that changes in the immune systems that occur
sion. These results suggest that antiorthostatic suspension of during or after space flight could contribute to possible
rats resulted in altered interferon production, a finding sim- compromised resistance to infectious diseases. These results
ilar to that observed when cosmonauts were tested for in- indicated that changes in immunological parameters in-
terferon production after space flight (75). duced by antiorthostatic suspension had the potential to alter
Similar results were observed when mice were suspended resistance to infection.
antiorthostatically (53). Using the mouse model, we were In view of the above findings, we had the opportunity to
able to add a control for orthostatic suspension. In this plan our first flight studies. Several rats were flown in
control for the stress of confinement and stress of suspen- SpaceLab-3, and experiments were carried out to determine
sion, mice were suspended in a harness with no head-down the effects of flight on cytokine production (21). The rats
tilt. Mice suspended for 12 wk in the antiorthostatic ori- were flown in the Space Shuttle for 7 d, and after landing,
entation showed severely inhibited interferon-/ produc- a transcontinental airplane flight and a 12-h delay occurred
tion compared with normally housed controls (53). Mice before sacrifice. This delay and flight could have affected
suspended in the orthostatic orientation showed no change the results we obtained. After sacrifice, spleens were re-
in interferon-/ production compared with controls (53). moved from the rats and place in individual cell culture. The
This suggested that the antiorthostatic orientation of suspen- cultures were then challenged with concanavalin-A to in-
sion was required for inhibited interferon / production, duce interferon-. After the appropriate time interval, the
i.e., the stress of suspension alone could not account entirely cultures were harvested and assayed for interferon- activ-
for inhibited interferon production. Mice suspended anti- ity. Interferon- production was reduced significantly in
orthostatically and then allowed to recover in normal caging cells taken from rats immediately after flight, compared
for 1 wk regained their capacity to produce interferon-/ with cells from control rats (21). This flight experiment
(53). A more recent study carried out in our laboratory has yielded a result similar to that observed after antiorthostatic
also indicated that interferon- production can be altered by suspension of rats and consistent with the impaired inter-
antiorthostatic suspension (4). feron production by cosmonauts after flight (75).
An additional suspension study using mice was carried Production of another cytokine, interleukin-3, was also
out by Fleming and associates (18). In this study, they measured in the same experiment on SpaceLab-3 used for
showed that mice suspended antiorthostatically had im- production of interferon- (21). Interleukin-3 plays a major
paired ability to produce superoxide, decreased ability to kill role as a growth factor for immunologically important cells.
phagocytosed bacteria (Propionibacterium acnes), and al- In this case, cells from rats flown in SpaceLab-3 showed the
tered corticosterone levels that did not correlate with im- same pattern of production of interleukin-3 as did cells from
munosuppressive effects of suspension (18). This indicated control rats (21). These data suggested that not all immu-
that antiorthostatic suspension could alter the inflammatory nological parameters are affected equally by space flight.
and phagocytic responses of the host. These data were not We were also fortunate to be able to participate in the
substantiated by others, who demonstrated no effect in a rat Cosmos #1887 Soviet space flight (64). In this case, we
suspension model (44). The apparently contradictory data extended our studies to other immunological areas. We
regarding suspension effects on inflammatory responses and carried out experiments to determine the effects of space
phagocytosis raises a theme that was previously described flight on the distribution of leukocyte subpopulations. The
regarding space-flight experiments. Sometimes, results ap- distribution of leukocyte subpopulations has been shown to
pear to be contradictory. This is probably due to specific be an important indicator of normal immunological func-
experimental conditions and complicating additional vari- tion, e.g., patients with acquired immune deficiency syn-
ables that occur. drome (AIDS) have an altered ratio of CD-4 T lympho-
In addition, we used the model to determine whether cytes to CD-8 T-lymphocytes (31). In our first set of
suspension resulted in alterations to resistance to infection. experiments, spleens were removed from 5 rats flown for
Female Swiss/Webster mice were inoculated with the D 12.5 d on biosputnik Cosmos #1887. The biosputnik landed
variant of encephalomyocarditis virus (EMC-D virus). off course, and a 48-h delay and a transcontinental airplane
EMC-D virus is a convenient virus to utilize, because al- flight occurred between landing and sacrifice of the rats.
teration in a glucose tolerance test is all that is necessary to This delay could have affected the results we observed. The
show successful infection with the virus. Females of the spleens were dissociated into individual cells, and separate
Swiss/Webster strain of mouse are normally resistant totally samples were stained with different antibodies directed
to infection with EMC-D virus (22). Resistance to EMC-D against markers on the surface of rat leukocyte populations.
virus is mediated, at least in part, by interferon (22). Anti- These antibodies were antiasialo GM-1 (natural killer cells),
IMMUNITY AND SPACE Medicine & Science in Sports & Exercise 2023
OX-39 (interleukin-2 receptor), OX-1 (pan-leukocyte mark- Control animals were euthanized at the same time on the
er), W3/25 (CD-4 T lymphocyte), OX-8 (CD-8 T-lym- ground, and tissues were maintained under similar condi-
phocyte), W3/13 (pan T-lymphocyte), OX-4 (polymorphic tions for the same duration as the flight samples. All sam-
la-class II histocompatibility antigen), antirat IgG Fab, an- ples were analyzed at the same time. Results indicated that
tirabbit IgG (irrelevant antibody control), and no antibody both leukocyte blastogenesis and natural killer cell activity
(negative control). The stained cells were then analyzed were inhibited in samples obtained during flight compared
using a flow cytometer. Although there may be problems with ground controls (33). This indicates that the actual
with nonspecific staining in these results, a trend suggesting in-flight conditions contributed to the effects of space flight
a dramatic shift in the following cell populations compared on the immunological parameters observed.
with synchronous (rats treated the same way as flight rats In another study, we carried out an experiment using
except for actual space flight) and ground controls: T- pregnant rats flown on the Space Shuttle. Immune responses
lymphocytes, CD-8 T-lymphocytes, and interleukin-2 re- of dams, fetuses, and pups (fetuses and pups obtained after
ceptor-bearing T-lymphocytes (64). The increase in inter- landing) were determined after landing (69). Interferon-
leukin-2 receptor-bearing T-lymphocytes could have production, leukocyte blastogenesis, and the response of
indicated an increased aberrant immunologic activity in- immature cells to colony-stimulating factor all showed
duced by space flight. However, this increased activity trends to inhibition in the dams but were unaffected in the
could have been held in check by the increased level of pups and fetuses (when observation was possible) (69).
CD8 T-lymphocytes. This altered ratio of T-lymphocyte These results suggest that the limited number of immune
subsets could also account for, at least in part, inhibited responses we observed in offspring of pregnant rats were not
blastogenic responses and interferon production reported affected by space flight.
previously after space flight and may be related to an altered Recent studies have been carried out by Chapes and his
TH-1/TH-2 cytokine profile. associates (9,10) to determine whether there could be inter-
Additional studies carried out on rats flown in Cosmos ventions that could prevent or ameliorate the effects of space
#1887 involved bone marrow cells. Due to the limited flight on the immune system. In one set of experiments (10),
number of bone marrow cells from the femur made available treatment of rats before and during flight with interleukin-2
to us, only two cell populations were examined in the bone was utilized to determine whether detrimental effects of
marrow, i.e., the total leukocyte population and the leuko- space flight on the immune system could be ameliorated. In
cytes carrying surface immunoglobulin. The analysis this case, space-flight conditions induced very small
showed a large number of myelogenous cells bearing sur- changes in the immune system of control rats, so the effects
face immunoglobulin from flown rats as compared with of interleukin-2 were difficult to evaluate. In another exper-
synchronous and ground control rats (64). Myelogenous iment, rats were implanted with chambers that released
cells are monocyte/macrophage precursors and would not insulin growth factor-1 and then subjected to space flight
have been expected to have a surface immunoglobulin (9). The results suggested that insulin growth factor-1 could
marker. In addition, the bone marrow cells were also tested lessen some of the effects of space flight on the immune
for their ability to respond to macrophage colony stimulat- system but that space flight can also affect the normal
ing factor (M-CSF). M-CSF stimulates the division of response to the growth factor. Therefore, amelioration of
monocyte-macrophage precursors (59). The bone marrow space flight effects on immune responses remains an area
cells from flown rats were inhibited in their ability to form that requires extensive future study.
colonies in the presence of M-CSF, indicating a lack of Although most studies carried out in our laboratory and
division on the part of those precursor cells (64). The data those of others on the effects of space flight on the immune
with the bone marrow cells suggested that an unusual re- system involved the use of rodents, there has been one
sponse for myelogenous cells to divide while they were still limited study involving the use of rhesus monkeys. We were
in the bone marrow of flown rats was induced by space also able to participate in limited studies with monkeys. In
flight and that those cells were refractory to additional a Russian Cosmos biosatellite mission, monkeys tested after
exogenous stimulation by M-CSF. Monocytes/macro- return to earth showed decreases in interleukin-1 produc-
phages, therefore, are immunologically important cells that tion, alterations in receptors for cytokines, and a decrease in
appear to be affected by space flight. the ability of bone marrow cells to respond to exogenous
We were able to repeat the experiments described above colony-stimulating factors (68). These results are similar to
for the Cosmos #1887 flight (64) during the Cosmos #2044 those observed in studies involving rodents and humans, and
flight in 1990. Analysis of the data suggests a similar pattern validate the use of the animal models for studying the effects
of results to those observed during the Cosmos #1887 flight of space flight on the immune system.
for both CSF and leukocyte-phenotyping studies (66). Ad- In view of the current limitations on space flight exper-
ditional studies indicated that natural killer cell activity was iments caused by construction of the International Space
also affected by space flight (54). We participated in an Station, we have again focused on AOH suspension as a
additional study carried out by A. Lesnyak, using rats that potential model for the effects of space flight on immune
were euthanized and dissected during a Space Shuttle flight responses and resistance to infection. During the Cosmos
(33). In this case, rats were euthanized 1 d before landing, 2044 flight, a parallel antiorthostatic suspension study was
and tissues were kept refrigerated until landing and analysis. carried out. In this case, antiorthostatic suspension of rats
2024 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org
resulted in similar results to those seen after space flight suspension on resistance to infection. This approach in-
with regard to the inhibited response of bone marrow cells volves the study of the effects of changes in levels of
to CSF but showed no correlation to the effects of space catecholamines, such as norepinephrine, on the invading
flight on subpopulations of leukocytes (66). pathogens. The possibility that an infectious organism may
Other groups have also carried out studies to determine respond to neuroendocrine signals, especially to those that
the effects of space flight and antiorthostatic suspension on are elaborated during periods of stress, should not seem that
immune responses. These results are, in general, similar to unlikely. Recent original work by Lyte and his associates
our own results on leukocyte subset distribution and com- (32,3537) and others establishing this principle has dem-
partmentalization of the effects of space flight on immune onstrated that the catecholamines can profoundly influence
responses (1,15,23,25,48 50). Additionally, an ability of the in vitro growth of gram-negative bacteria. Norepineph-
the antiorthostatic suspension to model effects of space rine, in particular, was shown to increase the growth of
flight on dynamic functional immune responses such as members of the Enterobacteriaceae and Pseudomona-
cytokine production but not on nondynamic immune param- daceae families by over four logs as compared with bacteria
eters such as leukocyte subset distribution has been con- cultured in control media. In addition to changes in growth,
firmed (1,4,15,23,25,48 50). Pecaut et al. (52) recently norepinephrine increased the production of virulence-asso-
demonstrated that rats flown in space had changes in leu- ciated factors on a protein equivalent basis as compared with
kocyte subset distribution and that ground-based modeling controls. Production of the Shiga-like toxins by Escherichia
did not show similar results. Therefore, despite its limita- coli 0157:H7 was found to be increased nearly 100-fold in
tions, the antiorthostatic suspension model is a very useful the presence of norepinephrine (38). Elaboration of the K99
model for studying the effects of recreating some of the pilus adhesin by the enterotoxigenic E. coli (ETEC) patho-
conditions occurring during space flight on immune re- gen B44, which is responsible for attachment of the bacte-
sponses and resistance to infection. rium to the intestinal wall, was increased over 1300-fold
To take additional advantage of this model, because it has (39). Culture of pathogenic bacteria in norepinephrine-con-
not been possible, to date, to carry out studies on the effects taining medium has also led to the discovery by Lyte and
of space flight on resistance to infection, we have carried out associates (37) of on of the first autoinducers of growth in
ground-based studies to determine the effects of AOH sus- bacteria. Importantly, this effect of catecholamines on bac-
pension on resistance of mice to bacterial infection with terial growth has been shown to be nonnutritional in nature
Listeria monocytogenes (43,45). We have been able to show (32,37).
that mice subjected to AOH suspension have enhanced Studies involving the use of and adrenergic agonists
resistance to primary infection with L. monocytogenes and antagonists, as well as the less physiologically active
(43,45). This was probably due to enhanced macrophage enantiomer of norepinephrine, ()-norepinephrine, sug-
function and cytokine production in eliminating the patho- gested that a non-, non- adrenergic receptor-mediated
gen (43,45). However, at the same time that resistance to process may play a role in norepinephrine-induced growth
primary infection was enhanced, the ability to generate of gram-negative bacteria (32).
long-term immunologic memory to the challenge organism In our laboratory, we have adapted this system to study
was decreased after 7 d of suspension (43,45). Therefore, additional pathogens (27). We have shown that cat-
although initial resistance was enhanced by AOH suspen- echolamines can enhance the growth of Aeromonas hy-
sion, the ability to develop long-term resistance to additional drophila, an opportunistic gram-negative bacterial pathogen
challenge with infectious organisms was compromised (27). Norepinephrine was the most effective catecholamine
(43,45). in this system, but epinephrine and dopamine were also
effective (27). We have also shown that a siderophore-type
mechanism may be involved in the interaction of cat-
THE NEUROENDORINE SYSTEM, THE IMMUNE
echolamines with bacteria, but confirmation will require
SYSTEM, AND SPACE FLIGHT
additional study (28).
It is well-established that exposure to stress can results in Stress can certainly play a role in the effects of space
alterations in immune responses and resistance to infection flight and AOH suspension on immune responses (70).
mediated by interaction of stress hormones from the sym- Stress would not be the only factor involved, as multiple
pathetic nervous system and the HPA axis with immune factors such as radiation exposure, microgravity exposure,
responses (62). Stress hormones, such as corticosteroids and and indirect effects from other body systems such as the
catecholamines, have been shown to interact directly with musculoskeletal system could also play a role; however, it
cells of the immune system and to influence development of will be important to isolate and identify the effects of stress
immune responses and the outcome of infections (62). Al- on resistance to infection to allow for future development of
though such interactions of stress hormones and the immune specific countermeasures. Although limited evidence to date
system occur, they cannot explain all effects of the stress of suggests that stress hormones such as corticosteroids may
space flight or AOH suspension on the immune system and not play a major role in the effects of space flight or AOH
resistance to infection (62). suspension on immune responses (18,30,51), the situation is
Recently, we have also begun to develop a new approach unclear with regard to catecholamines, but preliminary ev-
to study the effects of the stress of space flight and AOH idence does suggest some correlation with space flight-
IMMUNITY AND SPACE Medicine & Science in Sports & Exercise 2025
induced effects on immune responses (11). The area has not Current studies performed in the authors laboratory have been
been fully or carefully investigated (11), and it is possible funded by the National Aeronautics and Space Administration
(NASA) through the NASA Cooperative Agreement NCC 9-58 with
that stress-induced catecholamines could play a role in any the National Space Biomedical Research Institute and the National
alterations in resistance to infection induced by space flight Aeronautics and Space Administration (Cooperative Agreement
or AOH suspension. The effect could be on the host immune NCC2-1262).
responses or directly on the infectious organisms. This area
should be a potential fruitful subject for future investigation.

REFERENCES
1. ALLEBBAN, Z., A. T. ICHIKI, L. A. GIBSON, J. B. JONES, C. C. during long duration spaceflight on board the orbital MIR station.
CONGDON, and R. D. LANGE. Effects of spaceflight on the number Aviat. Space Environ. Med. 65:419 423, 1994.
of rat peripheral blood leukocytes and lymphocyte subsets. J. Leu- 21. GOULD, C. L., M. LYTE, J. A. WILLIAMS, A. D. MANDEL, and G.
koc. Biol. 55:209 213, 1994. SONNENFELD. Inhibition of interferon-gamma but normal interleu-
2. ARMSTRONG, J. W., R. A. GERREN, and S. K. CHAPES. The effect of kin-3 production from rats flown on the Space Shuttle. Aviat.
space and parabolic flight on macrophage hematopoiesis and func- Space Environ. Med. 58:983986, 1987.
tion. Exp. Cell Res. 216:160 168, 1995. 22. GOULD, C. L., and G. SONNENFELD. Enhancement of viral patho-
3. BECHLER, H., A. COGOLI, M. COGOLI-GREUTER, O. MuLLER, and E. genesis in mice maintained in an antiorthostatic model: coordina-
HUNZINGER. Activation of microcarrier attached lymphocytes in tion with effects on interferon production. J. Biol. Regulat. Ho-
microgravity. Biotechnol. Bioeng. 40:991996, 1992. meostat. Mech. 1:3336, 1987.
4. BERRY, W. D., J. D. MURPHY, B. A. SMITH, G. R. TAYLOR, and G. 23. GROVE, D. S., S. A. PISHAR, and A. M. MASTRO. The effect of a
SONNENFELD. Effect of microgravity modeling on interferon and 10-day space flight on the function, phenotype, and adhesion
interleukin responses in the rat. J. Interferon Res. 11:243249, molecule expression of splenocytes and lymph node lymphocytes.
1991. Exp. Cell Res. 219:102109, 1995.
5. BILLIAU, A. Interferon-I: General and Applied Aspects. Amster- 24. HAWKINS, W. R., and J. F. ZIEGELSCHMID. Clinical aspects of crew
dam: Elsevier Biomedical Press, 1984, pp. 271. health. In: Biomedical Results of Apollo, NASA-SP-368. Wash-
6. CAREN, L. D., A. D. MANDEL, and J. A. NUNES. Effect of simulated ington, DC: NASA, 1975, pp. 43 81.
weightlessness on the immune system in rats. Aviat. Space Envi- 25. ICHIKI, A. T., L. D. GIBSON, T. L. JAGO, et al. Effect of spaceflight
ron. Med. 51:251255, 1984. on rat peripheral blood leukocytes and bone marrow progenitor
7. CHAPES, S. K., D. R. MORRISON, J. A. GUIKEMA, M. L. LEWIS, and cells. J. Leukoc. Biol. 60:37 43, 1996.
B. S. SPOONER. Cytokine secretion by immune cells in space. 26. ILYAN, E. A., and V. E. NOVIKOVO. A stand for simulation of
J. Leukoc. Biol. 52:104 110, 1992. physiological effects of weightlessness in laboratory experimental
8. CHAPES, S. K., D. R. MORRISON, J. A. GUIKEMA, M. L. LEWIS, and rats. Space Biol. Med. 14:128 129, 1980.
B. S. SPOONER. Production and action of cytokines in space. Adv. 27. KINNEY, K. S., C. E. AUSTIN, D. S. MORTON, and G. SONNENFELD.
Space Res. 14:59, 1994. Catecholamine enhancement of Aeromonas hydrophila growth.
9. CHAPES, S. K., S. J. SIMSKE, A. D. FORSMAN, T. A. BATEMAN, and Microbial Pathogenesis 26:8591, 1999.
R. J. ZIMMERMAN. Effects of space flight and IGF-1 on immune 28. KINNEY, K. S., C. E. AUSTIN, D. S. MORTON, and G. SONNENFELD.
function. Adv. Space Res. 23:19551964, 1999.
Norepinephrine as a growth stimulating factor in bacteria: mech-
10. CHAPES, S. K., S. J. SIMSKE, G. SONNENFELD, E. S. MILLER, and R. J.
anistic studies. Life Sci. 67:30753085, 2000.
ZIMMERMAN. Effects of spaceflight and PEG-IL-2 on rat physio-
29. KONSTANTINOVA, L. V., and B. B. FUCHS. The Immune System in
logical and immunological responses. J. Appl. Physiol. 86:2065
Space and Other Extreme Conditions. Chur, Switzerland: Har-
2076, 1999.
wood Academic Publishers, 1991, pp. 258.
11. CHRISTENSEN, N. J., P. BRATHOLM, and J. H. KNUDSEN. Lymphocyte
30. KOPYDLOWSKI, K. M., D. S. MCVEY, K. M. WOODS, J. J. LANDOLO,
norepinephrine and epinephrine as indices of long-term changes in
sympathoadrenal activity in human subjects. J. Gravitational and S. K. CHAPES. Effects of antiorthostatic suspension and cor-
Physiol. 4:115116, 1997. ticosterone on macrophage and spleen cell function. J. Leukoc.
12. COGOLI, A., M. VALUCHI-MORF, M. MuLLER, and W. BREIGLEIB. The Biol. 52:202208, 1992.
effect of hypogravity on human lymphocyte activation. Aviat. 31. LA VIA, M. F., P. E. HURTUBISE, J. W. PARKER, et al. T-lymphocyte
Space Environ. Med. 51:29 34, 1980. subset phenotypes: a multisite evaluation of normal subjects and
13. COGOLI, A., A. TSCHOPP, and P. FUCHS-BUSLIN. Cell sensitivity to patients with AIDS. Diagn. Immunol. 3:75 82, 1985.
gravity. Science 225:228 230, 1984. 32. LENARD, J., and R. VANDEROEF. A novel bacteriostatic action of
14. COGOLI, A. The effect of hypogravity and hypergravity on cells of bovine and porcine serum that is reversed by norepinephrine. Life
the immune system. J. Leukoc. Biol. 54:259 268, 1993. Sci. 57:443 447, 1995.
15. CONGDON, C. C., Z. ALLEBBAN, L. A. GIBSON, et al. Lymphatic 33. LESNYAK, A., G. SONNENFELD, L. AVERY, et al. Effect of SLS-2
changes in rats flown on Spacelab Life Sciences-2. J. Appl. spaceflight on immunologic parameters of rats. J. Appl. Phsyiol
Physiol. 81:172177, 1996. 81:178 182, 1996.
16. CRUCIAN, B. E., M. L. CUBBAGE, and C. F. SAMS. Altered cytokine 34. LIMOUSE, M., S. MANIE, I. KONSTANTINOVA, B. FERRUA, and L.
production by specific human peripheral blood cell subsets im- SHAFFAR. Inhibition of phorbol ester-induced activation in micro-
mediately following space flight. J. Interferon Cytokine Res. 20: gravity. Exp. Cell Res. 197:82 86, 1991.
547556, 2000. 35. LYTE, M. The role of catecholamines in Gram-negative sepsis.
17. DURNOVA, G. N., A. S. KAPLANSKY, and V. V. PORTUGALOV. Effect Med. Hypotheses 37:255258, 1992.
of a 22 day spaceflight on lymphoid organs of rats. Aviat. Space 36. LYTE, M., and S. ERNST. Alpha and beta adrenergic receptor
Environ. Med. 47:588 591, 1976. involvement in catecholamine-induced growth of grain-negative
18. FLEMING, S. D., C. F. ROSENKRANS, Jr., and S. K. CHAPES. Test of bacteria. Biochem. Biophys. Res. Commun. 190:447 452, 1993.
the antiorthostatic suspension model on the inflammatory cell 37. LYTE, M., C. D. FRANK, and B. T. GREEN. Production of an
responses. Aviat. Space Environ. Med. 61:327332, 1990. autoinducer of growth by norepinephrine cultured Escherichia coli
19. GIRON, D. J., F. F. PINDAK, and J. P. SCHMIDT. Effect of a space 0157:H7. FEMS Microbiol. Lett. 139:155159, 1996.
cabin environment on viral infection. Aerosp. Med. 38:832 834, 38. LYTE, M., B. P. ARULANANDAM, and C. D. FRANK. Shiga-like toxins
1967. by Escherichia coli. 0157-H7 can be influenced by the neuroen-
20. GMUNDER, F. K., I. KNOSTANTINOVA, A. COGOLI, A. LESNYAK, W. docrine hormone norepinephrine. J. Lab. Clin. Med. 128:392398,
BOGMOLOV, and A. W. GRACHOV. Cellular immunity in cosmonauts 1996.

2026 Official Journal of the American College of Sports Medicine http://www.acsm-msse.org


39. LYTE, M., B. ARULANANDAM, K. NGUYEN, C. FRANK, A. ERICKSON, 61. SHEARER, W. T., J. M. REUBEN, J. M. MULLINGTON, et al. Soluble
and D. FRANCIS. Norepinephrine induced and expression of viru- TNF- receptor 1 and IL-6 plasma levels in humans subjected to
lence associated factors in enterotoxigenic and enterohemorrhagic the sleep deprivation model of spaceflight. J. Allergy Clin. Immu-
strains of Escherichia coli. Adv. Exp. Biol. Med. 412:331339, nol. 107:165170, 2001.
1997. 62. SHERIDAN J., F., C. DOBBS, J. JUNG, et al. Stress-induced neuroen-
40. MANDEL, A. D., and E. BALISH. Effect of spaceflight on cell docrine modulation of viral pathogenesis and immunity. Ann. N. Y.
mediated immunity. Aviat. Space Environ. Med. 48:10511057, Acad. Sci. 840:803 808, 1998.
1977. 63. SONNENFELD, G., E. R. MOREY, J. A. WILLIAMS, and A. D. MANDEL.
41. MEEHAN, R. T., L. S. NEALE, E. T. KRAUS, et al. Alterations in Effect of a simulated weightlessness model on the production of
human mononuclear leukocytes following spaceflight. Immunol- ray interferon. J. Interferon Res. 2:267270, 1982.
ogy 76:491 497, 1992. 64. SONNENFELD, G., A. D. MANDEL, I. V. KONSTANTINOVA, et al. Effects
42. MEEHAN, R. T., P. WHITSON, and C. SAMS. The role of pyschoneu- of spaceflight on levels and activity of immune cells. Aviat. Space
roendocrine factors on spaceflight-induced immunological alter- Environ. Med. 61:648 653, 1990.
ations. J. Leukoc. Biol. 54:236 244, 1993. 65. SONNENFELD, G., and G. R. TAYLOR. Effects of microgravity on the
43. MILLER, E. S., and G. SONNENFELD. Influence of suspension on the immune system. SAE Technical Paper Series No. 911515. War-
expression of protective immunological memory to murine Liste- rendale, PA: Society of Automotive Engineers, 1991, pp. 6.
ria monocytogenes infection. J. Leukoc. Biol. 54:378 383, 1993. 66. SONNENFELD, G., A. D. MANDEL, I. V. KONSTANTINOVA, et al.
44. MILLER, E. S., D. A. KOEBEL, S. DAVIS, et al. Effect of suspension Spaceflight alters immune cell function and distribution. J. Appl.
on neutrophil function in the rat. J. Appl. Physiol. 76:387390, Physiol. 73:191S195S, 1992.
1994. 67. SONNENFELD, G., J. MEASEL, M. R. LOKEN, et al. Effects of isolation
45. MILLER, E. S., and G. SONNENFELD. Influence of antiorthostatic on interferon production, hematological and immunological pa-
suspension on resistance to murine Listeria monocytogenes infec- rameters. J. Interferon Res. 12:75 81, 1992.
tion. J. Leukoc. Biol. 55:371378, 1994. 68. SONNENFELD, G., S. DAVIS, G. R. TAYLOR, et al. Effect of space-
46. MOREY, E., E. SABELMAN, R. TURNER, and D. BAYLINK. A new rat flight on cytokine production and other immunologic parameters
model simulating some aspects of spaceflight. The Physiologist of rhesus monkeys. J. Interferon Cytokine Res. 16:409 415, 1996.
22:S23S24, 1979. 69. SONNENFELD, G., M. FOSTER, D. MORTON, et al. Spaceflight and
47. MUSACCHIA, X. J., D. R. DEAVERS, G. A. MEININGER, and T. P. development of immune responses. J. Appl. Phsyiol. 85:1429
DAVIS. A new model for hypokinesia: effects on muscle atrophy in 1433, 1998.
the rat. J. Appl. Physiol. 48:470 476, 1980. 70. SONNENFELD, G. Immune responses in space flight. Int. J. Sports
48. NASH, P., B. BOUR, and A. M. MASTRO. Effect of hindlimb sus- Med. 19:S195S204, 1998.
pension simulation of microgravity on in vitro immunological 71. SONNENFELD, G. Extreme environments and the immune system:
responses. Exp. Cell Res. 195:353360, 1991. effects of spaceflight on immune responses. J. Allergy Clin. Im-
49. NASH, P., I. V. KONSTANTINOVA, B. B. FUCHS, A. RAKHMILEVICH, A. munol. 107:19 20, 2001.
LESNYAK, and A. M. MASTRO. Effect of spaceflight on lymphocyte 72. STEFFEN, J. M., R. ROBB, M. J. DOMBROWSKI, X. J. MUSACCHIA,
proliferation and interleukin-2 production. J. Appl. Physiol. 73: A. D. MANDEL, A. D., and G. SONNENFELD. A suspension model for
186S-190S, 1992. hypokinetic/hypodynamic and antiorthostatic responses in the
50. NASH, P., and A. M. MASTRO. Variable lymphocyte responses in mouse. Aviat. Space Environ. Med. 55:612 616, 1984.
rats after spaceflight. Exp. Cell Res. 202:125131, 1992. 73. STEFFEN, J. M., and X. J. MUSACCHIA. Thymic involution in the
51. NICOGOSSIAN, A. E., C. L. HUNTOON, and S. POOL (Eds.). Space suspended rat: adrenal hypertrophy and glucocorticoid receptor
Physiology, and Medicine, 2nd Ed. Philadelphia: Lea & Febiger, content. Aviat. Space Environ. Med. 57:162167, 1986.
1989, pp. 481. 74. STOWE, R. P., C. F. SAMS, S. K. MEHTA, et al. Leukocyte subsets
52. PECAUT, M. J., S. J. SIMSKE, and M. FLESHNER. Spaceflight induces and neutrophil function after short-term spaceflight. J. Leukoc.
changes in splenocyte subpopulations: effectiveness of ground- Biol. 65:179 186, 1999.
based models. Am. J. Physiol. 279:R2072R2078, 2000. 75. TALAS, M., L. BATKAI, L. STOGER, et al. Results of space experi-
53. ROSE, A., J. M. STEFFEN, X. J. MUSACCHIA, A. D. MANDEL, and G. ment program Interferon. I. Production of interferon in vitro by
SONNENFELD. Effect of antiorthostatic suspension on interferon- human lymphocytes aboard space laboratory Solyut-6 (Interferon
alpha/beta production by the mouse. Proc. Soc. Exp. Biol. Med. I) and influence of space flight on lymphocyte functions of
177:253256, 1984. cosmonauts (Interferon III). Acta Microbiol. 30:53 61, 1983.
54. RYKOVA, M. P., G. SONNENFELD, A. T. LESNYAK, et al. Effect of 76. TAYLOR, G. R. Recovery of medically important microorganisms
spaceflight on natural killer cell activity. J. Appl. Physiol. 73: from Apollo astronauts. Aerospace Med. 45:824 828, 1974.
196S200S, 1992. 77. TAYLOR, G. R. Overview of spaceflight immunology studies.
55. SCHMITT, D. A., C. PERES, G. SONNENFELD, et al. Immune responses J. Leukoc. Biol. 54:179 188, 1993.
in humans after 60 days of confinement. Brain Behav. lmmun. 78. TAYLOR, G. R. NASA Technical Memorandum 58252, Washing-
9:70 77, 1995. ton, DC: NASA, 1983, pp. 34 48.
56. SCHMITT, D. A., J. P. HATTON, C. EMOND, et al. The distribution of 79. TAYLOR, G. R., and J. R. DARDANO. Human cellular immune
protein kinase C in human leukocytes is altered in microgravity. responsiveness following space flight. Aviat. Space Environ. Med.
FASEB J. 10:16271634, 1996. 54(Suppl. 1):S55S59, 1983.
57. SCHMITT, D. A., L. SCHAFFAR, G. R. TAYLOR, et al. Use of bed rest 80. TAYLOR, G. R., L. S. NEAL, and J. R. DARDANO. Immunological
and head-down tilt to simulate space flight-induced immune sys- analyses of U.S. Space Shuttle crewmembers. Aviat. Space Envi-
tem changes. J. Interferon Cytokine Res. 16:151157, 1996. ron. Med. 57:213217, 1986.
58. SCIENCE MAGAZINE. 225(4658):163234, 1984. 81. TAYLOR, G. R., and R. P. JANNEY. In vivo testing confirms a
59. SHADDUCK, R. K., and N. G. NAGABHUSHANAM. Granulocyte colony blunting of the human cell-mediated immune mechanism during
stimulating factor. I. Response to acute granulocytopenia. Blood spaceflight. J. Leukoc. Biol. 51:129 132, 1992.
38:559 568, 1971. 82. VOSS, E. W., Jr. Prolonged weightlessness and humoral immunity.
60. SHEARER, W. T., D. J. LUGG, H. M. ROSENBLATT, et al. Antibody Science 225:214 215, 1984.
responses to bacteriophage phi X-174 in human subjects exposed 83. WOODS, K. M., and S. K. CHAPES. Abrogation of TNF-mediated
to the Antarctic winter-over model of spaceflight. J. Allergy Clin. cytotoxicity by space flight involves protein kinase C. Exp. Cell
Immunol. 107:160 164, 2001. Res. 211:171174, 1994.

IMMUNITY AND SPACE Medicine & Science in Sports & Exercise 2027