Prepared for 

THE LIFE SCIENCES DIVISION 

OFFICE OF SPACE SCIENCE AND APPLICATIONS 

NATIONAL AERONAUTICS AND SPACE ADMINISTRATION 

WASHINGTON, D.C. 20546 

under 

Contract Number NASW 3924 
RESEARCH OPPORTUNITIES ON 

IMMUNOCOMPETENCE IN SPACE 

December 1985 

Prepared for 

The Life Sciences Division 

Office of Space Science and Applications 

National Aeronautics and Space Administration 

Washington, D.C. 20546 

1 under 

Contract Number NASW 3924 

Edited by 

William R. Beisel, M.D. 

John M. Talbot, M.D. 

LIFE SCIENCES RESEARCH OFFICE 

FEDERATION OF MERICAN SOCIETIES 

FOR EXPERIMENTAL BIOLOGY 

9650 Rockville Pike 

Bethesda, Maryland 20814 

FOREWORD 

The Life Sciences Research Office (LSRO), Federation 

of American Societies for Experimental Biology (FASEB), provides 

scientific assessments of topics in the biomedical sciences. 

Reports are based upon comprehensive literature reviews and the 

scientific opinions of knowledgeable investigators engaged in 

work in specific areas of biology and medicine. 

This technical report was developed for the National 

Aeronautics and Space Administration (NASA) in accordance with 

the provisions of Contract Number NASW 3924. It was prepared 

and edited by William R. Beisel, M.D., of The John Hopkins School 

of Hygiene and Public Health, and John M. Talbot, M.D., Senior 

Medical Consultant, LSRO. 

The LSRO acknowledges the contributions of the investigators and consultants who assisted with this study. The report 

reflects the opinions expressed by an ad hoc Working Group that 

met at the Federation on July 25-26, 1985 and other consultants 

who contributed to the study. The study participants reviewed 

a draft of the report and their various viewpoints were incorporated into the final repor?. 

accept responsibility for the accuracy of the report: however, 

the listing of these individuals in Section VI does not imply 

that they specifically endorse each study conclusion. 

The study participants and LSRO 

The report was reviewed and approved by the LSRO 

Advisory Committee (which consists of representatives of each 

constituent Society of FASEB) under authority delegated by the 

Executive Committee of the Federation Board. Upon completion 

of these review procedures, the report was approved and transmitted to NASA by the Executive Director, FASEB. 

While this is a report of the Federation of American 

Societies for Experimental Biology, it does not necessarily 

reflect the opinion of each individual member of the FASEB 

constituent Societies. 

/.$YC 

Kenneth D. Fisher, Ph.D. 

Director 

Life Sciences Research Office 

iii 

SUMMARY 

bNeutrophilia, relative lymphopenia, and impaired 

blastogenic responsiveness of T-lymphocytes have been demonstrated repeatedly in postflight blood samples from space crews. 

These abnormalities of the cellular immune system apparently 

revert to preflight values within approximately one week 

postflight. Other space-related alterations of human immune 

function have been described such as postflight eosinopenia, 

monocytopenia, reduced percentage of B-lymphocytes, and decreased 

natural killer cell activity and production of a-interferon by 

lymphocytes. No consistent alterations of humoral immune function have been reported. The causes and mechanisms involved in 

these responses are unknown, nor is it known at which stages of 

flight the reported responses occur. 

Microbiologic assays of space crews and spacecraft 

suggest that interpersonal transfer of pathogenic bacteria 

and fungi occurs inflight along with increased growth of 

opportunistic microorganisms, spread of the normal skin flora 

to more body sites, and simplification of the anaerobic bacteria 

in the spacecraft. Bacterial contamination of air and onboard 

potable water supplies is a recognized potential source of 

illness. 

Whether the aforementioned changes in elements of the 

immune system and the microflora of space crews and spacecraft 

represent a significant, potential health problem for space crews 

needs to be determined. To date, resistance to infection during 

and following missions of up to seven months' duration has apparently been adequate. Episodes of inflight illness have generally 

been mild, brief, and readily controlled. Postflight illness 

attributed to impaired immunocompetence has not been reported. 

Currently, a paucity of reliable data on the effects 

of space flight on immunocompetence prevents a firm scientific 

conclusion about the potential operational and clinical significance of reported changes. The ad hoc Working Group participants 

regarded the following as the most significant of the available 

data: (1) reduced postflight blastogenic response of peripheral 

lymphocytes from space crew members; (2) postflight neutrophilia, 

persisting up to seven days; (3) gingival inflammation of the 

Skylab astronauts; (4) postflight lymphocytopenia, eosinopenia, 

and monocytopenia; (5) modifications and shifts in the microflora 

of space crews and spacecraft; and (6) microbial contamination of 

cabin air and drinking water. Discussion of these responses and 

other available data disclosed numerous gaps in knowledge that is 

essential for an adequate understanding of space-related changes 

in immunocompetence. These missing data are listed as questions 

in Section 111. 

V 
The ad hoc Working Group discussed the significance of 

the available data. For example, if the data on the altered 

blastogenic responsiveness of lymphocytes from postflight blood 

specimens are valid, this is an important change that needs 

precise explanation. Such an explanation might be an inability 

of T-lymphocytes to generate growth factors and growth factor 

receptors, suggesting marked dysfunction with implications for 

serious impairment of immunocompetence. Another example is the 

question of the functional condition of the circulating neutrophils. The gingivitis experienced in the Skylab Program could 

reflect neutrophil dysfunction such as impairrnent of cell surface 

adhesion reactions. Whether neutrophil function remains normal 

inflight and during the first few days postflight is unknown. 

In the opinion of the ad hoc Working Group, if NASA 

contemplates future studies of the immunologic aspects of space 

flight, first priority should be given to tests and experiments 

that could indicate whether space flight impairs cellular and 

humoral immunity. Pre-, in-, and postflight tests of space crew 

personnel would be mandatory parts of such a program. Despite 

the sophisticated studies that could be attempted, a clear-cut 

demonstration of normal cell-mediated immunity as measured 

by delayed dermal hypersensitivity reactions during and/or 

postflight along with normal inflight humoral responses to a 

defined antigen would alleviate many of the concerns that have 

been expressed on the basis of our current lack of knowledge. 

Finally, if further experience demonstrates that space 

flight does compromise immunocompetence, NASA should plan a 

series of investigations to determine the causes and mechanisms 

and develop methods of intervention. Specific approaches, tests, 

and methodologies that would aid in accomplishing these objectives are presented in Section IV. 

vi 
TABLE OF CONTENTS 

Page 

Foreword ...................... iii 

Summary ...................... V 

I . Introduction .................... 1 

A . Background .................. 1 

B . Objectives and Scope ............. 2 

I1 . Available Information on Immunologic Aspects 

of Space Flight ................. 3 

A . Data from Space Flight ............ 3 

1 . HumanData ................ 3 

2 . Animal Studies .............. 6 

B . Data from Ground-based Studies ........ 8 

C . Microbiologic Data ............... 9 

I11 . Opinions of the . ad hoc Working Group ........ 17 

A . Appraisal of Available Data .......... 17 

1 . Potentially serious immunologic and 

microbiologic changes .......... 17 

2 . Possible etiology and mechanisms ..... 18 

B . Significance of Available Data ........ 25 

C. Missing Essential Information ......... 26 

IV . Research Suggestions ................ 29 

A . Immediate Research Needs ........... 29 

B . Research Needs Should Space-Related 

Immunologic Changes Demonstrate 

Potentially Unacceptable Health Risks .... 30 

C . Tests and Methodologies ............ 34 

D . Facilities and Equipment ........... 36 

E . Concluding Remarks .............. 36 

V. Literature Cited .................... 37 

VI . Study Participants ................. 47 

vii 

I. INTRODUCTION 

A. BACKGROUND 

The National Aeronautics and Space Administration 

(NASA), through its various life sciences programs, conducts 

and supports scientific investigations of the biological changes 

that are associated with space flight. Among the effects whose 

causes and potential significance are not well understood are 

those involving the immune system. Few, if any, instances of 

inflight or postflight illnesses or other untoward effects have 

been ascribed to impairment of cellular immune function; 

neutrophilia, relative lymphopenia, and a diminished blastogenic 

responsiveness of T-lymphocytes present in postflight samples 

of blood obtained from the astronauts and cosmonauts have been 

observed repeatedly (Barone and Caren, 1984; Cogoli and Tschopp, 

1985; Kimzey, 1975a,b; 1977; Konstantinova et al., 1973; Pestov 

and Geratewohl, 1975; Taylor and Dardano, 1983). 

yet 

The humoral immune system has shown no detectable 

abnormalities in space flight on the basis of relatively limited 

studies, except for inconsistent variations in Complement Factor 

3 (C3) and immunoglobulin levels observed postflight. The microflora associated with space crew members as well as that of the 

interiors of spacecraft undergoes changes during flight; however, 

no adverse effects of these changes on crew health have been 

reported to date, Changes observed in the immune system and 

microflora of astronauts, in combination, raise the very real 

possibility that dangerous consequences could ensue in the 

future, especially when missions last for extended periods. 

NASA-supported research on the immunologic aspects 

of space flight has been modest in comparison with programs 

on other adverse biomedical phenomena such as space sickness, 

cardiovascular deconditioning, bone loss, and muscle atrophy. 

Reports of advisory groups such as the NASA Life Sciences 

Advisory Committee (Whedon, 1978) and the Space Science Board 

of the National Research Council (Bricker, 1979) have not 

emphasized space-related immunologic changes among topics 

identified for further research, Currently, NASA has no formal 

plan for generating extramural immunologic studies except for 

some limited experiments in the future Spacelab mission dedicated 

to the life sciences. 

science of immunology has progressed tremendously in the past 

decade. Immunologic advances and current testing methods render 

some previously acquired data on the immunologic aspects of space 

flight obsolescent and in need of reevaluation. A thorough 

evaluation of available data and expert judgment on the health 

and safety implications of space-related alterations in immune 

functions are necessary to determine the possible need for additional state-of-the-art investigation in immunology. Therefore, 

NASA requested that the Life Sciences Research Office of the 

However, it should be recognized that t 

1 
Federation of American Societies for Experimental Biology undertake a review of its research program and research needs in 

relation to immunologic effects and microbial flora changes 

during space flight. This report is based upon the opinions and 

suggestions of an ad hoc Working Group of knowledgeable scientists (E Section VI) whose members met at the Federation on 

July 25-26, 1985, and other experts who contributed data and 

refinements. 

B. OBJECTIVES AND SCOPE L 

The objectives of the LSRO study are: 

(1) to review extant knowledge of the subject; 

(2) to examine NASA's current and projected research 

program; 

(3) to identify significant gaps in essential 

knowledge; 

(4) to formulate additional suggestions for future 

research consideration by NASA; and, 

(5) to produce a documented report of the foregoing 

items that can be used for NASA research 

program planning. 

The scope of the study includes a review of available 

data on immunologic and microbiologic responses observed from 

inflight as well as ground-based investigations, changes in 

humoral and cell-mediated limbs of the immune system, stress and 

neuroendocrinologic immune modulation, nutritional influences, 

neutrophils, monocytes and macrophages, activators and modulators, possible therapeutic intervention, and investigational 

techniques, methods and facilities. This report incorporates the 

opinions of the members of the ad hoc Working Group on the practical significance of space-related immunologic changes in future 

long-term space missions including the Space Station and the 

additional studies needed to establish whether the observed 

changes imply potentially serious consequences for space crews. 

2 
11. AVAILABLE INFORMATION ON IMMUNOLOGIC ASPECTS OF SPACE FLIGHT 

A. DATA FROM SPACE FLIGHT 

1. Human Data 

Prior to the time when published data became 

available from the Skylab series of manned space missions 

(December 1972 to February 19741, alterations of some indices 

of immunologic function in space-flown animals, astronauts, and 

cosmonauts had been reported (Berry, 1974; Konstantinova et al., 

1973; Vorobyev et al., 1983). Data suggested that both animal 

and human subjects demonstrated postflight neutrophilia and 

either lymphopenia or lymphocytosis. Transient neutrophilia, 

reversible by the second postflight day, was observed in the 

Apollo astronauts. NASA space medical specialists considered 

that the neutrophilia probably resulted from increased blood 

epinephrine and steroid levels associated with mission stress 

(Berry, 1974), but other causes must be considered. Postflight 

lymphocyte counts tended toward a delayed but fluctuating increase. The immunocompetence of the Apollo astronauts' lymphocytes, estimated by in vitro response to mitogenic stimulation, 

was considered unimpaired (Berry, 1974). 

In the Skylab Program, indices of humoral immunity 

measured in pre-, in-, and postflight blood specimens of the 

astronauts (i-e., plasma immunoglobulins and complement factors) 

were within normal limits except for a slight decrease in C3 

levels in postflight samples. No significant changes were found 

in related plasma proteins such as transport proteins, protease 

inhibitors, and other plasma proteins except for elevated levels 

of a -macroglobulin and, in two of the three crewmen of Skylab 2 

(28-8 mission), a slight increase in lysozyme levels that persisted for several days (Kimzey, 1977; Kimzey et al., 1975b). 

No studies have been performed to determine how humoral immunity 

would respond to standardized antigenic stimuli. At recovery, 

the Skylab astronauts demonstrated an increase in the absolute 

white cell count, reflected by increased numbers of neutrophils. 

There were no significant changes in the absolute numbers of 

lymphocytes, but T-lymphocytes were depressed (Kimzey, 1977). 

Several measures of the functional capacity of the T-cell component of the cellular immune system were done in the Skylab 

Program: (1) blast transformation of purified lymphocytes by 

in vitro mitogenic challenge with phytohemagglutinin (PHA); (2) 

mixed lymphocyte cultures; and (3) rosette formation by lymphocytes with sheep erythrocytes. Results from Skylab missions 

2 and 3 (28- and 59-d respectively) showed a depression of RNA 

synthetic response to PHA on the day of recovery (R+O) with 

return to preflight values within 3-7 d. The decrease in RNA 

responsiveness was less pronounced in lymphocytes from the crew 

of Skylab 4 (84-d). DNA production in response to PHA appeared 

to be depressed in seven of the nine crew members (Kimzey, 1977); 

however, Taylor and Dardano (1983) indicated that the depression 

3 
of DNA synthesis rates was not significant. The mixed lymphocyte 

culture responses were within normal limits, and the E-rosette 

test indicated a reduced number of circulating T-lymphocytes on 

R+O, with return to normal levels by R+3 d (Kimzey, 1977). 

Comparison of pre-, in-, and postflight classes of 

immunoglobulins (IgG, IgM, IgA, IgE, and IgD) of four crew members who participated in the 10-d Spacelab 1 mission (November 28 

to December 8, 1983) revealed only minor fluctuations that were 

considered insignificant (Voss, 1984). The experimental protocol 

included control studies for circadian rhythm effects and a 

sampling of 20 Caucasian males for normative data. The results 

substantiate the findings in the Skylab program of essentially 

no influence of space flight on immunoglobulin concentrations 

(Kimzey, 1977). 

The reactivity of lymphocytes from two cosmonauts 

to T-cell mitogenic stimulation was reported as depressed to 

apprbximately 42% of preflight values following a 63-d Salyut-4 

space mission (Konstantinova et al., 1978). Similar results were 

reported from Soviet missions of 5, 30, and 140, but not of 96 

days' duration (Cogoli and Tschopp, 1985; Konstantinova et al., 

1973). On day R+2, one of the crew of the 63-d mission showed 

a 4-fold reduction in numbers of T-lymphocytes as estimated by 

nonspecific rosette formation with sheep erythrocytes. By R+7, 

T-lymphocyte levels were normal. IgA content of blood taken on 

R+2 was decreased 3.8-fold in one and 6- to 7-fold in the other 

crew member, with a tendency toward normalization by R+7. This 

had not been observed in previous Soviet and United States space 

missions (Konstantinova et al., 1978). The authors also reported 

sensitization of lymphocytes to staphylococcal and streptococcal 

"allergens" of the "main representatives of human automicroflora" 

by three methods: (1) lymphocyte specific blast transformation; 

(2) inhibition of macrophage migration; and (3) intracutaneous 

injection of 0.1 ml of four "allergens" on R+15, with examination 

of the local skin reaction after 24 and 48 h. 

Pre- and postflight measurements of blood from 

cosmonauts in a series of space missions showed in a majority 

of instances a postflight leukocytosis and lymphocytopenia 

(Konstantinova et al., 1978; Legen'kov et al., 1977). Noting 

that previously used methods had made detailed reappraisal and 

comparison of results of earlier studies impossible, Taylor and 

Dardano (1983) reported the results of tests of lymphocyte transformability in which a modification of Apollo and Skylab met odology was used. The method permitted direct correlation of 'J3 

thymidine uptake with incubation time as well as mitogen concentrations. Lymphocytes from astronauts who flew in the first 

four Shuttle flights (durations varied from 2-8 d) demonstrated 

a significant reduction in blastogenic responsiveness ranging 

from approximately 39 to 82% of mean preflight values. In 

addition, immediate postflight neutrophilia and a decreased 

number of eosinophils were observed (Taylor and Dardano, 1983). 

In six of the eight subjects tested, the lymphocyte blastogenic 

4 
reactivity remained depressed at R+3 to R+5 relative to preflight 

values; however, the trend was toward normalization. The ad hoc 

Working Group regarded this as the best of the studies reported 

to date on the effects of space flight on human lymphocyte 

blastogenic responsiveness. 

Finally, human lymphocytes exposed inflight in culture 

to mitogenic concentrations of Concanavalin A (ConA) during the 

Spacelab 1 mission demonstrated less than 3% of the levels of 

activation of ground control samples (Cogoli and Tschopp, 1985; 

Cogoli et al., 1984). 

The Soviet flights in the period 1977-1981 in the Salyut 

6-Soyuz program involved 30 cosmonauts and included five 2-man 

missions of 96, 140, 175, 185, and 75 days' duration (Vorobyev 

et al., 1984). The authors reported consistent postflight immunologic changes including a decrease in blood T-lymphocytes and 

diminished reactivity and capacity for proliferation of these 

cells. Blood studies of the cosmonauts following the 185-d 

flight showed reductions in T-helper and natural killer cells, 

with unchanged suppressor activity. These indices gradually 

returned to normal during readaptation on Earth. No serious 

inflight illnesses were reported. 

Postflight values of serum C3 were elevated following 

16-, 18-, and 49-d Salyut missions; C4 levels were unchanged 

except for a significant increase in the 49-d mission (Guseva 

and Tashpulatov, 1979, 1980). Pronounced postflight increases 

in serum concentrations of IgA, IgG, and IgM were reported from 

the 49-d flight (Cogoli, 1981). 

During the first few postflight days of the 140-d Salyut 

6-Soyuz mission (MC-21, blood from the two cosmonauts showed a 

marked decrease in T-lymphocytes, which normalized by postflight 

day 7 (Yegorov, 1979); however, after the 175-d mission (MC-31, 

this index was depressed in only one of the two crewmen (Yegorov, 

1980). After both missions, the responsiveness of the T-lymphocytes to blastogenic transformation by PHA was depressed. This 

index had normalized by postflight day 24 of MC-2 (time of second 

blood sampling) and by postflight day 8 in the commander of MC-3. 

Early postflight depression of serum IgG values was reported in 

one of the two crew members in the MC-2 mission (Yegorov, 1979) 

and apparently in one member of the MC-3 crew (Yegorov, 1980). 

Minimal evidence of inflight development of delayed hypersensitivity to "microallergens" of the normal flora of the 

body (staphylococcus and streptococcus) and to chemicals 

(formaldehyde) was presented based on inconsistent, slight 

increases in production of leukocyte migration inhibiting factor 

and on delayed dermal hypersensitivity responses (Yegorov, 1979, 

1980). The author concluded: "The regularity of the changes in 

immunological reactivity found after long space flights confirms 

the need to search for means and methods of returning it to 

normal. 'I 

5 
In general, the inflight clinical condition of the 

astronauts and cosmonauts has remained good (Berry, 1974; 

Nicogossian and Parker, 1982; Vorobyev et al., 1983, 1984). 

Inflight infections and inflammations of the skin, conjunctiva, 

mouth, nose, throat, and larynx of the 27 Apollo astronauts are 

listed in Table 1 (Berry, 1974). These medical problems were 

mostly mild, self-limited, or responded promptly to treatment. 

instances of mild dermatitis, one sty, one incipient axillary 

furuncle, and a brief episode of unilateral serous otitis were 

reported (Hordinsky, 1977). Mean scores for gingival inflammation and dental calculus approximately doubled over preflight 

values; but the degrees of change were less in Skylab 3 (59-d), 

and, in no case was there dental or oral disability (Brown et 

al., 1977). However, it is noteworthy that careful oral hygiene 

was maintained by all the Skylab astronauts before the missions, 

including removal of all dental plaque and calculus on preflight 

day 4. 

Among the total nine astronauts in Skylab, three 

In summary, the results of a series of investigations 

of the effects of space flight on various aspects of human 

immunocompetence commencing with blood counts in the earliest 

missions and progressing to measurements of several indices of 

cellular and humoral immunity suggest that space flight induces 

some changes in immunocompetence, the best documented being 

suppression of T-lymphocyte numbers and blastogenic transformation. 

2. Animal Studies 

Hypoplasia of spleens and thymus glands with 

reduced numbers of cells in the splenic red and white pulp 

as well as decreased numbers of lymphocytes in the cortex of 

thymus glands of 14 rats flown in space fo,r 22-d were reported 

by Durnova et al. (1976). Structural recovery of the lymphoid 

organs approached normal by postflight day 27 except for delayed 

recovery of the splenic mantle zones composed of small lymphocytes. Ground-based experimental controls subjected to simulated 

space flight conditions (except for weightlessness and acceleration) showed qualitatively similar, but quantitatively lesser, 

histologic changes in the lymphoid organs; splenograms from 

simulated flight rats did not show the changes induced by 

space flight. 

Splenic lymphocytes from rats flown in space for 20-d 

did not show a decreased blastogenic activity when compared with 

ground controls; instead, they demonstrated an increased responsiveness to the nonspecific mitogens PHA and ConA as well as 

certain specific and nonspecific antigens (Mandel and Balish, 

1977). The findings did not support a hypothesis that a 20-d 

space flight may cause degradation of cell-mediated immunity. 

6 
Table 1. Apollo Inflight Medical Problems 

Symptoms/Findings Etiology 

Number of 

Occurrences 

Inguinal rash 

Inguinal rash 

Urinary tract infection 

associated with prostatic 

congestion 

Conjunctival injection 

Eye irritation 

Skin irritation 

Skin irritation 

Respiratory irritation 

Recurrence of facial rash 

Stomatitis 

Stomatitis 

Rhinitis 

Laryngitis 

Barotitis 

Coryza 

Seborrhea 

Dermatitis, pustular 

Collection device 

Tricophyton rubrum 

Pseudomonas aeruqinosa 

Spacecraft atmosphere 

Fiber glass 

Fiber glass 

Biosensor sites 

Fiber glass 

Contact dermatitis 

Aphthous ulcers 

Undetermined 

Oxygen and low humidity 

Undetermined 

Barotrauma 

Undetermined 

Activated by spacecraft 

environment 

Biosensor sites 

4 

1 

2 

9 

1 

1 

1 

1 

2 

1 

1 

3 

2 

2 

Adapted from Berry, 1974 

7 
However, the authors noted that the small number of animals in 

each experimental group and the large standard deviations in the 

data indicated a need for replication of the experiments and 

caution in interpretation of the results. 

B. DATA FROM GROUND-BASED STUDIES 

Six healthy male subjects were kept at strict horizontal 

bed rest for 62 d during which three of the subjects performed 

daily physical exercises, On test days 1 and 18 all subjects, 

and on day 50 three subjects, were exposed to transverse acceleration on a centrifuge (Mikhaylovskiy et al., 1967). After 

day 46, blood properdin was detectable in only one subject. A 

17-26% decline in neutrophil phagocytosis occurred in the three 

nonexercising men. Toward the end of the test period, saliva 

lysozyme activity decreased 5 to 8-fold compared with initial 

levels, and, between days 13 and 33, the bactericidal activity 

of the skin decreased, again predominantly in the nonexercising 

group. The authors noted a parallelism between hypokinesia and 

susceptibility to "inflammatory ailments" (for example, rhinopharyngitis, follicular angina, acute periodontitis). 

In a 56-d ground simulation of a Skylab mission in which 

the environmental factors essentially duplicated those of the 

Skylab orbiting station except for weightlessness, radiation, 

and accelerations of launch-orbit and deorbit-reentry, no change 

in the reactivity of small lymphocytes of the three-man crew was 

demonstrable (Ritzmann and Levin, 1973). 

Human lymphocytes exposed to 1.8% of 1 G by rapid 

rotation in a clinostat were 50% less active in response to 

ConA mitogenic stimulation than 1 G controls (Cogoli et al., 

1980). Based on their own investigations and analyses of other 

reports on gravitational biology, the authors suggested that 

hypogravity depresses, whereas hypergravity enhances lymphqcyte 

activation by mitogens. 

Several investigators have reported the effects on 

susceptibility of experimental animals to certain infectious 

organisms resulting from exposure to environmental variables 

in simulated closed environments (Angrick et al., 1974; Giron 

et al., 1967; Gillmore and Gordon, 1974; Gordon and Gillmore, 

1974a,b). For example, in a study of the effects of a simulated 

space cabin environment on host resistance to infection, mice 

were subjected to a chamber barometric pressure of 380 mm Hg 

(18,000 ft equivalent) at 43% oxygen partial pressure (ground 

equivalent) before, during, or after challenge by intraperitoneal 

injection of a mengovirus suspension (Giron et al., 1967). Four 

groups of 100 mice were exposed to the test environment in the 

space cabin; the other two groups remained at ground level: (1) 

experimental group A remained at ground level before, during, and 

after an intraperitoneal injection of a mengovirus suspension; 

(2) group B was injected at ground level, then taken to the test 

8 
environment of 18,000 ft equivalent; (3) group C remained in the 

test environment for 2 wk, then was injected and kept at ground 

level; (4) group D was kept in the test environment before, 

during, and after injection; (5) group E was kept in the test 

environment, then brought to ground level for 1 h for injection 

and returned to altitude; and (6) group F animals were kept at 

altitude, brought to ground level for injection, kept there for 

24 h, then returned to altitude. Groups B, C, and E, but not 

group D, demonstrated increased susceptibility to the viral 

infection compared with controls. Group F animals, which were 

exposed to increased barometric pressure at ground level for 

24 h following injection, did not show a significant change 

in susceptibility. Thus, increased susceptibility in these 

experiments was associated with either an increase or a decrease 

of ambient barometric pressure by 380 mm Hg. The authors noted 

that even temporary and apparently minor changes in environmental 

conditions may alter host resistance (Giron et al., 1967). 

Rats were suspended in harnesses in a head-down position 

with forepaws touching the bottom of the enclosure to simulate 

some of the aspects of weightlessness (Caren et al,, 1980; Morey, 

1979). They were immunized with sheep erythrocytes and kept in 

the antiorthostatic, hypokinesic, hypodynamic mode for selected 

periods of up to 23 d for studies of antibody response, serum 

immunoglobulins, spleen and thymus weights, hematocrit, and white 

cell differential counts. In comparison with untreated cage 

controls, thymus glands were smaller in the experimental group 

(N=21) and a group of harnessed, weight-bearing controls (N=20). 

Otherwise, no significant differences were observed among the 

experimental and control groups (Caren et al., 1980). 

When compared with conventionally housed controls, 

rats subjected to simulated weightlessness for 2 wk by means 

of the same model (Morey, 1979) showed an 80% decline in 

interferon production when challenged with polyriboinosinicpolyribocytidylic acid (Sonnenfeld et al., 1982). Ivanov et al. 

(1983) exposed 3-year-old Macaca mulatta monkeys to 7- to 12-d 

periods of hypokinesia in a head-down position; before entering 

the antiorthostatic position, two animals spent 2 d in a primate 

chair, and three were subjected to clinostatic hypokinesis for 

7 d. After sacrifice, both experimental groups demonstrated a 

significant rise in serum complement activity and a decline in 

heterophil antibodies to ram erythrocytes. The authors inferred 

that an increase in complement content reflects adaptation to 

head-down tilt and a decrease in heterophil antibodies, an 

inhibition of B-lymphocytes. 

C. MICROBIOLOGIC DATA 

Numerous microbiologic studies have been done during 

United States and Soviet space programs. These have varied in 

scope and comprehensiveness, tending to emphasize the bacteria 

and fungi and to omit the viruses. In different missions, 

9 
microbial data were obtained from cultures of specimens including 

interior cabin surface swabs, samples of air and water, and swabs 

from skin and mucus membranes of the crews. These data are 

organized chronologically in the following paragraphs. The 

potential importance of the observed microbiologic changes must 

be evaluated with due consideration given to the immunologic 

effects of space flight. 

Studies of the microflora of the Apollo astronauts 

before and after the space flights showed that interpersonal 

transfer of pathogenic bacteria and fungi occurred regularly, 

that growth of opportunistic organisms seemed to be favored, 

and certain organisms showed decreased antibiotic resistance 

postflight (Berry, 1973, 1974). Berry (1973) listed the 

following changes from pre- to postflight: 

0 Decrease in anaerobic 0 Tendency for intercrew 

Staphylococcus aureus) 

0 Increase in numbers and 

bacteria microbial transfer (e.g., 

types of aerobic bacteria 0 Decrease in fungal isolates 

with microorganisms for Mycoplasma 

0 Increase in body sites 0 Increased carrier states 

Potential pathogens in the throat, especially Candida albicans, 

were present before, during, and after Apollo missions. SDecies 

of Proteus, Pseudomonas, and other pathogens increased markedly 

on the urine collectors. Trichophyton rubrum was linked with 

chronic dermatitis of one Apollo astronaut, and species of 

Haemophilus and Pseudomonas with urinary tract infections in 

two others (Berry, 1973, 1974). Microbiologic assessment in the 

Apollo Program included characterization of the viral and mycoplasma flora of the crew members and serologic assays for antibodies to approximately 13 specific viral antigens and two viral 

groups (ECHO and adenovirus). In addition, viral identification 

was done pre- or postflight when crew members had signs or symptoms of illness (Ferguson et al., 1975). Unusual episodes of 

viral illnesses were not experienced in the Apollo missions. 

Viral assays have apparently not been done in subsequent United 

States space programs. 

During the Apollo 16 mission, spores of Bacillus 

thurinqiensis were exposed to space flight conditions to 

determine the effects on viability and ability to produce 

toxins, Exposure to full sunlight resulted in decreased 

viability whereas the spacecraft environment without light 

or with solar irradiation at peak wavelengths of 254 and 

280 nm did not change viability, Postflight toxin production 

did not differ statistically from that of ground-based controls 

(Simmonds et al., 1974). 

10 
Sampling and analysis of the spacecraft atmosphere 

during a 56-d simulated Skylab mission revealed no consistent 

changes in concentrations or types of airborne microorganisms 

(Brockett and Ferguson, 1975). Microbiologic studies of the 

Skylab astronauts and their orbital workshop and command modules 

done before, during, and after the flights generally corroborated 

the findings in earlier manned space flights: 

tion of the Skylab environment, microbial simplification of 

anaerobic bacteria, intercrew transfer of pathogens, and no 

evidence of postflight "microbial shock" (defined on p.15) 

(Taylor et al., 1977). Swab and gargle samples from 10 body 

sites, urine and fecal specimens, cabin air, and surface samples 

were collected before, during, and after each mission. Inflight 

concentrations of bacteria in the air of Skylab 2 and 3 were 

low, but a relatively high concentration occurred in Skylab 4, 

attributable to contamination by Serrat'ia marcescens. 

organism was subsequently recovered as a new colonizer from all 

three Skylab 4 astronauts and was shown to have colonized the 

nasal mucosa of one crew member. 

gross contaminaThis 

Compared with preflight levels, inflight surface 

contamination by aerobic bacteria was low in the first manned 

mission (Skylab 2) and nearly doubled in Skylabs 3 and 4. 

Inflight anaerobic surface contamination more than doubled 

preflight levels in Skylab 2, increased 5-fold by mission day 

54 in Skylab 3, and approximated'preflight values in Skylab 4, 

the latter condition having been caused by the loss from the 

bacteriologic milieu of Proprionibacterium acnes, reflecting a 

diminution of the occurrence of this species in the skin of the 

astronauts (Taylor et al. , 1977 1. Infiight fungal isolations 

from surfaces in Skylab 2 were unremarkable, more than double 

preflight levels at day 57 in Skylab 3, and increased about 

10-fold in Skylab 4, which was subsequently traced to "mildewed" 

liquid-cooled garments stowed aboard Skylab. The investigators 

concluded that mission duration up to 84 d (Skylab 4) does not 

correlate with gross numerical changes in the autoflora, viable 

aerobic bacteria tend to increase in total numbers, anaerobes to 

decrease, and, while the numbers of aerobic genera and species 

change little, the numbers of anaerobic types decrease. Inflight 

cross-contamination, colonization, and infection with S. aureus 

were demonstrated in the Skylab series, corroborating previous 

reports of intercrew transfer of pathogenic organisms in missions 

lasting up to 18 d (Ferguson et al., 1975; Taylor, 1974). 

Yegorov (1979) listed general conclusions from microbiologic studies in some earlier flights of the Soyuz series and 

the Salyut orbiting station: 

0 Changes in total numbers of representatives 

of normal microflora of the skin 

0 Appearance on upper respiratory tract mucus 

membranes of organisms not normally present 

11 
0 Increased number of foci of pathogenic microflora 

on the skin of carriers 

0 Temporary colonization by pathogenic staphylococci 

on mucous membranes of previous noncarriers by 

intercrew microbial exchange 

0 Tendency toward increased virulence of pathogenic 

autof lora 

0 Increased concentration of microorganisms including 

certain pathogens in cabin air and on internal 

surfaces 

0 Apparent development of microbiologic and 

immunologic conditions favoring increased 

susceptibility to postflight infections, 

Marked inflight changes in the species composition of 

the microflora of the upper respiratory tract were found in the 

MC-1 cosmonauts (96-d mission), but not in the MC-2 crew who 

showed, in addition, no significant changes in their dermal 

autoflora (Yegorov, 19.79). In MC-3, there was a moderate increase in numbers of staphylococci in the nasal passages of one 

crew member. On the day of landing and 4 d later, the numbers 

of pathogenic staphylococci and 6-hemolytic streptococci in the 

mouths and throats of the MC-2 crew were very high, but had 

normalized by postflight day 7. Phage typing of oral specimens 

of staphylococci provided some evidence of probable intercrew 

exchange; however, there was no evidence of exchange in the MC-3 

cosmonauts (Yegorov, 1980). As in the MC-1 and MC-2 expeditions, 

microflora appeared in the mouths and throats of the MC-3 cosmonauts that were not normally indigenous: Streptococcus faecalis, 

Klebsiella pneumoniae, and Enterobacter hafnia. These findings 

were ascribed to weakening of local mucosal immunity. No remarkable postflight changes were observed in the microflora of the 

gastrointestinal tract. For example, at 3 d postflight, the 

intestinal flora of the MC-3 cosmonauts showed no shifts 'I*.. 

against a background of Bifidobacterum stability ...I* which had 

been achieved by preflight use of the drug, "Biphydumbacterin," 

and by inflight use of an amino acid/vitamin supplement (Yegorov, 

1980). Technical details of the drug and the nutritional supplement were not reported. 

Medical microbiology of the crews of the first four 

orbital test flights of the Shuttle was done as a part of the 

medical program to maintain the health and safety of the crew 

members (Pierson, 1983). Samples were collected at about 30, 

10, and 2 d preflight and on the day of recovery and postflight 

day 5 from ears, nose, throat, and rectum (or a fecal specimen) 

and a morning urine specimen. Interior surfaces of the spacecraft, cabin air, and waste management systems were sampled 30 

and 2 d prelaunch and on recovery day, and the potable water 

12 
system was sampled following servicing for flight and 3 d postflight, In addition, random samples of food stores onboard the 

orbiter were analyzed. The four flights, each with a crew of 

two, were all in the spacecraft Columbia, and their durations 

were from 2+ to 8 d. Tables 2 and 3 list microflora isolated 

from the samples. 

Although a variety of potential pathogens is evident 

from the list in Table 2, no overt clinical manifestations of 

infections were observed in the crews nor was there evidence 

of cross-contamination between members of the 2-man crews 

(Pierson, 1983). However, after landing in the third mission, 

bacteria present in the cabin air were also isolated from the 

upper respiratory mucosae of the crew, who had not shown the 

presence of these forms in preflight samples (species were not 

identified in Pierson, 1983). This finding emphasized the need 

for careful monitoring of the cabin air. During the sampling 

periods of the potable water supply, the numbers of colony- 

-forming units ranged from 5 to 9100 per 100 ml water. 

The effects of living and working in isolated environments on the microbiologic and immunologic defenses of the 

inhabitants are of interest as partial analogues of spacecraft 

environments. Moreover, there is some evidence that certain 

viral pathogens may persist undetected in carriers for many 

weeks until conditions favor their activation. For example, 

two outbreaks of respiratory tract illness occurred in a group 

of 18 personnel at 8 and 20 wk following total isolation at South 

Pole Station, Antarctica (Parkinson et al., 1980). In a similar 

environment, outbreaks of common colds occurred 17 wk after complete isolation of an Antarctic station party, long after the 

accepted incubation periods of human respiratory viruses and 

at a time when the introduction of new viruses was apparently 

impossible (Allen et al., 1973). In both of these studies, 

the investigators were unable to recover the causative viruses 

from specimens collected during the outbreaks. Another partial 

analogue of the environment of a spacecraft is the submarine. 

In typical 60-d patrols in Polaris nuclear submarines, the 

reported pattern of acute respiratory illness, based upon 10 

years' experience, indicated a maximum prevalence during the 

3-wk refit period when crews mingled with shore personnel. This 

was followed in one reported instance by a short secondary peak 

during the second week of patrol (Tansey et al., 1979; Watkins, 

1970). In most crews, the prevalence of acute respiratory illness remained low throughout the patrol. However, there are two 

reports of mid-patrol outbreaks of respiratory infections in 

nuclear submarine crews, one attributed to long incubation of the 

offending agent, the other to activation of an unidentified virus 

(Sawyer and Sommerville, 1966; Watkins, 1970). These data from 

Antarctica and the two mid-patrol outbreaks of acute respiratory 

illness in nuclear submarine crews raise important questions 

about the possible persistence and reactivation of respiratory 

(and other) viruses in space flights of long duration, especially 

if immunosuppression reduces the re.sistance of crew members. 

13 
Table 2. Potential Pathogens from Shuttle Crew Members 

Potential Pathogens Isolation Site 

Staphylococcus aureus 

Pseudomonas aeruginosa 

Enterobacter aerogenes 

Streptococcus 

Candida albicans 

Candida parapsilosis 

Asperqillus (six species) 

Klebsiella pneumonia 

Proteus morqanii 

Penicillium citrinum 

Rhodotorula rubra 

haf nia 

Nose, throat, 

Nose, throat 

Nose, throat 

Throat 

Throat 

Throat, feces 

Nose, ear 

Nose, throat, 

Throat 

Nose 

Urine, feces 

Ear 

ear 

ear, feces 

Source: Pierson, 1983 

Table 3. Potential Pathogens from Shuttle Spacecraft and 

Potable Water System after Four OFT* Missions 

Interior Surfaces Potable Water Supply 

Staphylococcus aureus 

Drechslera hawaiiensis 

Rhodotorula rubra 

Paecilomyces variotti 

Trichosporon cutaneum 

Geotrichum candidum 

Enterobacter aqglomerans 

Aspergillus (six species) 

Acinetobacter calcoaceticus 

Pseudomonas denitrificans 

Pseudomonas fluorescens 

Pseudomonas sp. 

Flavobacterium sp. 

Enterobacter sp. 

Rhodotorula minuto 

Source: Pierson, 1983 

* orbital flight test 

14 
The term, locked flora, relates to a type of isolation 

in which a host organism, such as a mammal, remains in a locked 

environment in which sterile food, water, and air are provided 

and there is no exogenous microbial contamination (Balish et al,, 

1977). As reviewed by Luckey (19661, a series of studies of 

animals with locked flora which were reported during the period 

1895-1965, generally showed a marked decrease in the numbers of 

intestinal species, with disappearance of many organisms. In 

some studies, only one or two bacterial species and perhaps one 

yeast could be isolated from intestinal sites. Luckey (1966) 

reviewed the anticipated anatomic, physiologic, and biochemical 

changes associated with simplification of the microflora. These 

included the possibility of microbial shock, which was defined 

by the author as "the precipitous and harmful action of microorganisms and/or their products upon the host." Maintenance 

of a normal, diversified intestinal microflora was considered 

essential as a host defense mechanism; apparently this requires 

periodic reinoculation of microorganisms. The author suggested 

ways of maintaining a balanced intestinal microflora during space 

flight in order to prevent possible microbial shock after return 

to Earth (Luckey, 1966). 

In a study to test the hypothesis that the microbial 

flora of mammals might change markedly toward simplification 

in an isolated environment, Balish et al. (1977) investigated 

the microbiology of beagles maintained in a locked environment 

(sterile food, water, and air, and no exogenous microbial contamination) for 30 mo. The results indicated that long-term 

confinement of beagles in such an environment was associated with 

increased diversity of the microflora. In comparison with nonisolated controls, larger populations of anaerobes, staphylococci 

(mainly S. epidermidis) and Candida albicans were observed in the 

isolated-beagles. Conversely, the control dogs showed larger 

populations of aerobic and facultative bacteria (Balish et al., 

1977). The data suggested to the investigators a decreased 

capacity of the intestinal microbial flora of the isolated dogs 

to inhibit the growth of potential pathogens. According to the 

authors, such a response in long-term space flight could represent a serious infectious threat for the crew. 

Conclusion 

Although microbiologic assays of spacecrews, spacecraft, 

and associated systems and equipment continue to be done as a 

part of medical surveillance, space medical authorities in the 

United States and the Soviet Union have, in recent years, apparently regarded the possible need for additional basic investigations of the microbiologic aspects of space flight as low in 

priority. 

15 

111. OPINIONS OF THE AD HOC WORKING GROUP 

A, APPRAISAL OF AVAILABLE DATA 

NASA scientists provided the LSRO ad hoc Working Group 

on Immunocompetence in Space with information and data from the 

United States and Soviet Union on the immunologic and microbiologic aspects of space flight, The participants examined 

pertinent data, and assessed the available information in terms 

of its scientific validity and adequacy for use in manned space 

programs , 

1. Potentially Serious Immunoloqic and Microbioloqic 

Chanqes 

The cumulative experience with the health of space 

crews in terms of resistance to infections during and following 

missions of up to 7 mo duration has apparently been favorable 

to date. Episodes of inflight illness have been mild, brief, 

and readily controlled. Postflight illness that might involve 

impaired immunocompetence has not been documented (Berry, 1974; 

Dietlein, 1977; Nicogossian and Parker, 1982; Vorobyev et al., 

1983, 1984). However, longitudinal studies of possible changes 

in immunocompetence have been neither extensive nor complete. 

The Working Group emphasized the paucity of data on 

immunologic functions in space. However, if the data on altered 

blastogenic responsiveness of lymphocytes (PHA response) are 

valid, this is an important change. The data are consistent 

in showing abnormal effects, some of which persist for at least 

7 d postflight. The most recent data represent an excellent, 

careful study of the PHA response featuring such refinements 

as different doses of PHA and different time points to check 

proliferation (Taylor and Dardano, 19831, Despite the results 

obtained in this study, the PHA response is a crude test, The 

results could mean nothing more than a slight, clinically insignificant decline in the numbers of T-cells in the peripheral 

blood. Conversely, for example, if the impaired PHA response 

represents a pronounced inability of the cells to generate 

lymphokines or lymphokine receptors, it is potentially important, 

especially for long-term flights. In view of the variations in 

this response in past studies of cosmonauts and astronauts, and 

the relatively small number of subjects involved to date, 

additional validation of the PHA data is needed. 

Postflight neutrophilia has been observed consistently. 

Of itself, the postflight neutrophilia is not necessarily important; that is, it could well be a physiologic response to elevated circulating stress hormones associated with the critical 

processes of reentry and landing on Earth (Berry, 1974). However, the question whether neutrophils are abnormal in the 

neutrophilia is very important as is the companion question 

pertaining to the lymphocytes. 

K ly0T li;f 17 
Some of the in vitro data are also potentially important 

such as the impaired production of a-interferon by lymphocytes 

taken from cosmonauts after 7 d in space (Talas et al., 1983) and 

the marked depression of blastogenic responses of human lymphocytes flown in Spacelab 1 (Cogoli and Tschopp, 1985). However, 

the participants noted that Cogoli and Tschopp (1985) carried 

out a very limited study, and no positive controls were used. 

The question of in vitro changes in lymphocyte blastogenesis, 

conducted in space, should be considered unresolved at this time. 

The importance of space-related effects on the immune 

system could exceed that of other biomedical effects of space 

flight because, in some circumstances, the microbiologic environment in spacecraft and crew could become hazardous in the 

presence of impaired immunocompetence. There is some evidence 

of a relative increase in potential pathogens during flight and 

of intercrew microbial transfer. For example, malfunction of 

the food or human waste management systems could allow growth of 

microorganisms that could overcome the immunological competence 

of space crew personnel. 

Other relevant facets of microbiologic-immunologic 

relationships in space flight involve the incomplete knowledge 

of the characteristics of changes in the microflora of crew and 

surroundings in space flight. More data are needed on such questions as simplification of the flora in restricted, isolated 

circumstances; persistence of potential pathogens, intercrew 

microbial exchange; and the influence of inflight microfloral 

changes on host resistance. 

2. Possible Etioloqy and Mechanisms 

Environmental factors and certain biologic 

responses to space flight that possibly influence immunologic 

functions are listed below; the related opinions and concepts 

of the Working Group are noted. The participants emphasized 

that the cause(s) of the observed changes in lymphocytic 

responsiveness and in numbers of circulating lymphocytes and 

neutrophils postflight is unknown. Whether such changes are 

of practical importance must await further elaboration of what 

happens to the immune system during space flight. 

0 Environmental physical factors such as microgravity, 

accelerations, and space radiation 

0 Physiologic and psychologic factors and "stress" 

- adaptive responses to 0-G: loss of approximately 

2.0 1 body fluid, decreased plasma volume, altered 

hemodynamics and lymph flow, bone loss, muscle 

atrophy, cardiovascular deconditioning, etc. 

- nutritional and metabolic disturbances 

- altered fluid/electrolyte/hormonal balances 

18 
must be 

- confinement, hypodynamia, hypokinesia, reduced 

- lack of privacy, social isolation, boredom 

- perceived danger, anxiety 

- problems of crew leadership, cohesion, and 

oxygen demand 

compatibility 

Increased osteoclastic activity at the expense of 

other cell types including lymphocytes and monocytes 

Sequestration of T-lymphocytes that are capable of 

blastogenic transformation 

Abnormal splenic hemodynamics and function 

Inhibition of helper factors 

Enhancement of suppressor factors 

Changes in bone marrow metabolism related to altered 

bone marrow hemodynamics 

Discussion and Opinion 

The aggregate of the psychophysiologic stress effects 

somewhat unique when one considers the limited human 

experience with microgravity and the environment of space 

flight and the unusual accelerations of launch-orbit and deorbitreentry. Although the stresses associated with space flight are 

not well defined in terms of their biologic effects, they have 

been proved operationally acceptable in view of the successful 

accomplishment of manned space missions lasting up to 7 mo. 

A majority of space medical experts apparently regard the net 

effect of such stresses as physiologically acceptable in the 

absence of overt functional impairment. During uncomplicated 

space flights, the combined stresses are probably of moderate 

degree, but with considerable individual variability in responses. For example, during the immediate prelaunch period, 

some spacecrew members experience heart rates of 120-160; others 

remain around 60. The reported changes in levels of stress 

hormones during space flight appear unremarkable in terms of 

possible effects on the immune system. However, available 

inflight data do not exclude the possibility of a surge in 

secretion of stress hormones and other neurohormones sufficient 

to cause substantial immunologic changes that are probably 

undetectable in spot blood samples or 24-h urine collections. 

Psychologic factors are believed by some investigators to 

influence immune regulation (Anonymous, 1985; Bartrop et al., 

1977; Chang, 1984; Park et al., 1971; Poteliakhoff, 1985). 

The subject of psychoneuroendocrinologic modulation of immunity, 

while a relatively new field of special investigation, is 

attracting numerous adherents (Blalock and Smith, 1985; 

Plotnikoff and Murgo, 1985; Riley, 1981; Rose, 1980; Spector, 

1983 1. 

19 
The members of the Working Group noted the vagaries 

associated with use of the term, stress, and emphasized the need 

for improved definition and characterization of stress responses 

during space flight, While such assessments are hampered by 

lack of precise methodology, the traditional physiologic and 

biochemical indices and the flight surgeon's appraisal of stress 

effects should be retained in NASA's study protocols in order 

to expand the data bases. Additional measurements should be 

considered so that a practical stress assessment protocol may 

be developed and put into practice. Voice analysis, expert 

behavioral observation by video or photography, intention tremor, 

and performance tests are candidate methods (Christensen and 

Talbot, 1985). 

Further to the subject of psychoneuroendocrinologic 

influences, the in vitro production of an ACTH-like peptide by 

mouse lymphocytes infected with Newcastle disease virus, and 

other experimental evidence have suggested the existence of a 

lymphoid-adrenal axis (Blalock and Smith, 1985). The molecule 

appears to be identical with ACTH, and the ACTH receptor from the 

lymphocytes appears to be identical to ACTH receptors on cells 

of the adxenal gland, If interactions of the neuroendocrine and 

immune systems prove to be additive or involved in cybernetic 

regulatory loops, it may become feasible to measure these 

interactive endocrine and nervous system functions (possibly 

including some stress effects) via fluorescence microscopic 

analysis of receptors on lymphocytes. Other methods to assess 

these molecules and interactions include: radioimmunoassays, 

Western blotting, and messenger RNA analysis such as cytoplasmic 

RNA dot blotting. These methods of measuring such molecules 

could be used in future studies of possible direct correlations 

between stress effects and altered immune function in space 

crews. 

Nutritional imbalances, particularly those involving 

deficient protein, energy, vitamin, zinc, and iron status, are 

known to affect immunocompetency (Beisel et al., 1981; Gershwin 

et al., 1985). Transient deficiencies of these and other nutrients as a result of loss from the body, sequestration, or diminished intake occur during generalized febrile illnesses, and may 

even accompany common infections, such as colds. Moreover, the 

losses of red blood cell mass, bone mineral, and lean body mass 

that occur in space flight, while not clinically debilitating in 

missions lasting up to 7 mo, could conceivably alter essential 

aspects of nutrition in flight members. These changes in turn, 

could lead to immunoincompetence of varying degrees and forms. 

The Working Group members noted that spacecrew meals contain 

quantities of micronutrients based on the U.S. Recommended 

Dietary Allowances (National Research Council, 1980). Under 

normal flight conditions, these should provide adequate dietary 

intakes. However, adequate in vivo data on indicators of nutritional status such as serum zinc and iron concentrations and 

those of other essential trace nutrients during space flight 

are not available. 

20 
Whether microgravity exerts a direct effect on the 

immune system is essentially unknown. Results of some experiments suggest that it does, but it is not feasible, based on 

available data, to exclude other variables that may contribute 

to such effects as the depressed blastogenic responsiveness of 

human lymphocytes flown in Spacelab 1 (Cogoli and Tschopp, 1985) 

or the enhanced inflight production of interferon by human 

lymphocytes and the reduced natural killer cell activity and 

interferon production of lymphocytes from cosmonauts following 

a 7-d flight (Talas et al., 1983). As mentioned in Section II-A, 

the impairment of blastogenic responsiveness of lymphocytes from 

postflight samples of space crew members' blood appears to be 

well documented by both U.S. and Soviet observers (Taylor and 

Dardano, 1983; Yegorov, 1979, 1980). Such space-associated 

changes in lymphocyte responsiveness are potentially important 

if they reflect something more than a slight decrease in the 

number of T-cells in the peripheral blood, such as an inability 

to produce interleukin-2 receptors. From a practical point of 

view, establishing that space flight induces important functional 

changes in the cellular elements of the immune system is probably 

a more pressing matter than determining the exact cause although 

both types of information are needed. 

Radiation 

The records of exposures to ionizing radiation to date 

indicate that inflight dose rates and total doses have been well 

within the operational safety limits employed by NASA (National 

Research Council, 1970). The crude mean total dose in the ten 

Apollo translunar missions, each lasting an average of 9.3+ d, 

was approximately 0.43 rad (Bailey, 1975). In the 84-d Skylab 4 

mission, the mean dose was 7.8 rad, and in eight Space Shuttle 

missions, the overall mean total dose was 0.42 rad (Benton et 

al., 1984). Estimated crew exposures for the 90-d Space Station 

mission range from 15-20 rad, and for a l-y mission to Mars, 

approximately 200 rad. Based on the 20 rad estimate, an average 

daily dose of approximately 220 mrad in the Space Station nearly 

matches the recommended limit for bone marrow, falls within the 

limit for eye lens and skin, but exceeds the limit for testis 

(National Research Council, 1970). 

For obvious reasons, no experimental data are available on 

the hematologic effects of prolonged, continuous, low-dose, whole 

body exposures of human subjects to low-LET (linear energy transfer) radiation such as gamma radiation. Consequently, animal 

data must be used for estimating probable biologic effects of 

low-dose irradiation during space flight. For example, as 

reviewed by Casarett (19691, dogs, mice, rats, and rabbits 

chronically exposed (e.g., ,100 wk in rabbits, 79 wk in mice, 

24 wk in guinea pigs) to whole body gamma or x-irradiation showed 

persistent depression of blood lymphocyte counts at 0.5, 2.2, 

>l.O, and 2.2 R/d; and of neutrophil counts at 3.0, 4.4, 10, and 

21 
>lo R/d respectively. In guinea pigs, lymphocyte counts declined 

at 0.11 R/d and neutrophil counts at 2.2 R/d (Casarett, 1969). 

Dogs exposed to brief daily doses of x-irradiation 6 d/wk at 

rates extending from 0.1 to 10.0 R/d demonstrated no significant 

change in blood lymphocyte counts during 2 y of exposure at 

0.1 R/d, but a substantial decrease at 0.5 R/d. Blood neutrophil 

count was mildly depressed after 1 y at 1.0 and 3 R/d but not at 

0.1 or 0.5 R/d (Casarett, 1969). 

More recently, Seed et al. (1984) reported some of the 

hem 010 ic effects of continuous, lifetime exposures of beagles 

to Co gamma irradiation. At 4 R/d absorbed dose, two of 25 

animals developed aplasia, 11 showed myeloproliferative disorders, and one, a lymphoproliferative disorder. In animals 

with these disorders, median times to death, respectively, were: 

1462 d, 1435 d, and 2076 d. The authors noted that transitions 

in lethality rates during continuous, very low dose-rate radiation exposure (defined as 5 R/d) probably result from the sparing 

of lymphohematopoietic function which appeared to prevent 

aplastic anemia and septicemias and to enable a time-dependent 

development of late-arising, nonhematopoietic syndromes such as 

solid tumors and degenerative disorders in long-term survivors. 

At 5 R/d such late-arising syndromes were similar in type and 

frequency to those in the nonirradiated controls. At the 5 R/d 

rate of exposure, the hematopoietic progenitor cells appeared to 

acquire radioresistance (Seed et al., 1984). 

8lj 

The members of the Working Group were of the opinion that 

radiation exposures of the magnitudes and durations experienced 

thus far in manned space missions would probably not account 

for the reported space-related changes in the immune system. 

Nevertheless, they recognized that little is known about several 

aspects of this subject, such as the possible influence on 

immune competence of the high energy (HZE) and high charge (Z>2) 

particle components of cosmic radiation, the combination of 

environmental factors in space flight with low-dose, continuous 

radiation, or the reliability of extrapolating animal data to 

human beings. 

In 1984, NASA commissioned an extensive review of the 

biomedical problems of space radiation by the National Council 

on Radiation Protection and Measurements. It is understood that 

the results of the review will be used for revising recommended 

permissible limits for use in the Space Station and other manned 

space programs. 

Interactions of Cells of the Immune System. Postflight flow 

cytometry of crew members' blood after Shuttle missions STS 41-B 

and 41-D (N=ll) showed a reduction in percentage of B-lymphocytes 

and monocytes. Monocytes and macrophages interact importantly 

with lymphocytes via lymphokines and monokines as well as by 

direct contact. Whether these factors have anything to do with 

immunologic changes in space flight is unknown. With respect 

to stress effects, under in vitro conditions, corticosteroids 

22 
in reasonably physiologic concentrations can inhibit both 

synthesis and secretion by macrophages and other cells of the 

immune system of a variety of materials such as interferons, that 

are involved in immunologic functions, Decreased monocyte counts 

may reflect a reduction in production rate in the bone marrow or 

possibly a change in numbers of monocytes in marginating pools in 

the blood vessels. Gamma-interferon produced by helper T-cells 

is an important modulator of macrophage activity, in part because 

it stimulates a complex system which leads to toxic oxygen intermediates that are involved in both intra- and extracellular 

killing mechanisms. 

T-lymphocytes interact with other cell types in generating the immune response, including macrophages, B-cells, and 

other non-T-lymphocyte accessory cells. In tissue culture and 

probably in vivo, cluster formation involving T-cells, B-cells, 

and macrophages is required for initial T-cell activation and 

subsequent development of the full immune response. Certain 

steps in the activation of T-lymphocytes apparently require 

direct cell-cell physical contact while other steps require 

humoral factors acting at short or long distances. Moreover, 

activation of T-cells apparently requires physical interaction 

with a non-T accessory cell, usually a macrophage or monocyte 

(Unanue, 1981). Whether the weightlessness of space flight 

adversely influences cell-cell physical interactions is unknown. 

The recent in vitro demonstration that human T-lymphocytes were 

evidently not activated inflight by ConA as they were in paired 

ground level controls suggests possible impairment of cell-cell 

physical interaction (Cogoli and Tschopp, 1985); however, the 

ad hoc Working Group considered it unlikely that microgravity 

would interfere with the agglutination process initiated by 

ConA in a lymphocyte culture. Interpretation of these data is 

obscured because the experiments lacked an adequate positive 

control. These controls could be generated, for example, by 

means of a macrophage-depleted culture of lymphocytes with added 

ConA and phorbol esters. 

Neutrophils. A consistent finding appears to be a postflight 

neutrophilia. It has traditionally been attributed to an 

elevation of stress hormones especially during the critical 

phases of atmospheric reentry and landing (Berry, 1973, 1974). 

In recent Shuttle flights, the numbers of neutrophils were 

doubled; this size of an increase is characteristic of the 

release of the marginated pool, Such neutrophilia can be 

induced experimentally by exercise or adminstration of epinephrine. Thus, the reported elevation of blood epinephrine may be 

a correct explanation for the release of the marginated pool of 

mature neutrophils. Increases in band forms were not reported, 

which suggests that elevated concentrations of corticosteroids 

were probably not involved in causing the neutrophilia. The 

cause of the neutrophilia is somewhat clouded by its reported 

persistence postflight for approximately 7 d, which suggests 

that epinephrine is not a fully suitable explanation because 

the normal turnover of h eutrophils is rapid, - 7 h. 

23 
Whether the neutrophils retain normal function during 

space flight is an important and unresolved question. Presumably, they do remain normal in view of the generally favorable 

record of good health of space crews. However, the good health 

of space crews may be deceptive because patients with severe 

neutrophil dysfunction can go months or even years without 

a major infection, only to die of an overwhelming microbial 

infection at a later date. The gingivitis reported in the Skylab 

series (Brown et al., 1977) could reflect neutrophil dysfunction 

such as an impairment of cell surface adhesion reactions or 

chemotactic and phagocytic responsiveness (Cogen et al., 1983). 

For example, even though white blood cell counts may be two 

to three times normal (magnitude similar to space-associated 

neutrophilia), patients with recurrent, severe, bacterial 

infections associated with functional deficiencies of their 

neutrophils, such as a deficiency of the C3bi receptor in which 

the cells lose their ability to stick and agglutinate, have 

severe gingivitis. The blood neutrophil count in these patients 

is twice normal, similar to those of space crews. For details 

of this type of deficiency, the reader is referred to Anderson 

et al. (19851, Arnaout et al. (19851, and Springer (1985). 

Severe neutrophil problems are associated with severe 

gingivitis whereas patients with life-threatening disorders who 

have normal neutrophils do not have gingivitis. The gingivitis 

reported in the Skylab astronauts was described as nondebilitating but as "... prominently elevated increments of ... gingival inflammation postflight as compared with preflight 

values" (Brown et al., 1977). There is no evidence that the 

Skylab astronauts experienced severe functional disorder of their 

neutrophils; nevertheless, the occurrence of gingival inflammation suggests that transient impairment of neutrophil function 

may have occurred. It is important to determine whether abnormal 

neutrophil function occurs in space flight, for, in long-term 

missions, impaired neutrophil function could be disastrous. 

Accordingly, the cause of the gingivitis in the Skylab astronauts 

deserves an adequate explanation. Suggestions for evaluating 

the functional status of neutrophils are presented in Section IV. 

Factors that Influence Microbiologic Chanqes. Well-known 

features of the space flight environment that contribute to 

microbiologic changes include the confined living space and 

crowding, closed recirculating cabin atmosphere, suboptimal human 

waste disposal, and lack of opportunity for customary quality and 

amounts of personal hygiene such as frequent bathing and changes 

of clothing. The enforced crowding presumably favors exchange of 

microflora among crew members. Inadequate microbial containment 

in the spacecraft is another deficiency as exemplified by reports 

of the escape of human and animal excreta into the living and 

working environment. Some of these factors may be amenable to 

improved engineering of environmental control and waste disposal 

systems. 

24 
, 

The effects of such "locked" environments on human 

autoflora are not clear. In animal studies, the phenomenon of 

locked microbial flora reportedly results in simplification of 

the intestinal flora (Luckey, 1966). However, Balish et al, 

(1977) observed increased diversity of the intestinal microflora 

of beagles that were kept in an isolated environment for 30 mo. 

Theoretically, marked simplification of, for example, the gastrointestinal microflora would deprive the host of part of the antigenic challenge that is considered necessary for maintaining 

immune competence. 

There is some evidence of simplification of the 

anaerobic bacteria in the microflora of the air in spacecraft 

(see - p.10-111, which apparently results from continuous 

recirculation through the filters and carbon dioxide adsorber 

beds of the environmental control systems. 

B. SIGNIFICANCE OF AVAILABLE DATA 

It is apparent that a decision by NASA management to 

establish a comprehensive research and analysis program in 

immunocompetence would require convincing evidence of a definite 

probability that space crews in future missions would experience 

clinically significant immune dysfunction. To determine whether 

such a probability exists, gaps in essential information must be 

filled. These are outlined in Section 111-C, 

The participants regarded the following as the most 

significant of the available data: 

0 Reduced postflight blastogenic response of 

peripheral lymphocytes from space crew members 

0 Postflight neutrophilia persisting for up to 7 d 

a Gingival inflammation in the Skylab astronauts 

0 Postflight lymphocytopenia, eosinopenia, and 

monocytopenia 

0 Modifications in microflora of crews and spacecraft 

0 Bacterial contamination of air and drinking water 

As previously noted, the impaired postflight response of 

lymphocytes to blastogenic activation by PHA is of major concern 

if it reflects lymphocyte dysfunction such as the inability to 

generate essential growth factors and growth factor receptors. 

A dysfunction of this sort persisting during the course of many 

months could compromise immunocompetence. The persistent postflight neutrophilia does not appear to result simply from 

increases in stress hormones. If it represents a functional 

25 
abnormality of the neutrophils, this could lead to the breakdown 

of host defenses against microbial infections. The gingivitis 

that occurred in the Skylab series is consistent with impaired 

neutrophilic cell-surface reactions. 

Although supporting data are scanty, the apparent 

disappearance of monocytes from the peripheral blood is extremely 

important if it reflects a true depletion of this essential cell 

type. Unpublished data from recent Shuttle flights appear inconsistent in that monocytes were observed in standard differential 

preparations but not by flow cytometry. Finally, the bacterial 

contamination of Shuttle drinking water (Pierson, 1983) which 

was observed during the first three orbital flight tests of the 

Columbia spacecraft is of obvious concern. It is understood that 

NASA is attempting to correct this deficiency in order to meet 

its set standard of a microbe-free drinking water supply. 

Similar attention should be paid to contamination of the air. 

C. MISSING ESSENTIAL INFORMATION 

For a variety of reasons, the program of investigakion 

of the immunologic aspects of manned space flight has been 

inadequate. However, as reviewed in Section 11, a number of 

studies of the subject, some of which were of high quality, 

have provided useful data and some concepts for future research 

planning. Nevertheless, competent judgment of whether spacerelated immunologic and microbiologic changes have finite 

clinical and operational implications is hampered by lack 

of knowledge, the most significant elements of which may be 

identified by the following questions: 

Because there are very few reliable basic data, the ' 

question remains: Does space flight cause untoward 

effects on the immune system? 

* During a space mission, when does the blastogenic 

responsiveness of the crew members' lymphocytes change? 

0 What happens to the white blood cell (WBC) count 

during space flight? When does the neutrophilia 

commence? What changes occur in the WBC differential 

picture? Do immature forms of neutrophils appear in 

peripheral blood? What happens to the lymphocyte 

differential distribution? 

What factors influence the depressed incorporation 

of thymidine by lymphocytes in response to mitogenic 

stimulation? Are humoral factors or changes in cell 

composition involved? Is autologous serum needed 

in vitro to reproduce the blunted PHA response? 

26 
a What happens to the functional capacities of 

neutrophils, monocytes, and macrophages? Do they 

retain normal chemotactic, phagocytic, bactericidal, 

and receptor-generating abilities and the ability to 

produce and release their important bioactive factors? 

a Do monocytes and eosinophils really disappear 

from the peripheral blood? If so, why? 

a How long do the following persist postflight: 

neutrophilia, lymphocytopenia, monocytopenia, 

eosinopenia, and the depressed blastogenic 

responsiveness of the lymphocytes? 

0 Are delayed-type hypersensitivity reactions 

normal during space flight? 

a What is the prevalence of infectious diseases in 

space crew members during the first 2 mo postflight? 

a What happens to viral parameters during space flight 

such as intracrew exchanges, changes in virulence, 

numbers, and possible contamination of air, water, 

and food? 

a What happens to body stores of essential trace 

nutrients and minerals, such as zinc and iron that 

can influence the immune system? 

a What happens to mucosal immunity in the conjunctivae, 

nose, oropharynx, larynx, trachea, bronchi, and the 

gastrointestinal and genitourinary tracts? Do organrelated lymphoid tissues such as those in the gut IGALT) 

and skin (SALT) undergo alterations? 

a Does microgravity itself affect the immune system? 

a Does gingivitis continue to occur during space 

flights? What are its incidence and duration? 

Is it attributable to trauma from preflight dental 

hygiene procedures, neutrophil dysfunction, or other 

identifiable factors? 

a Are there laboratory signs of previously unrecognized 

subclinical infections among crew members immediately 

after landing and after several days to weeks postflight? Laboratory tests for probing these questions 

might include red cell sedimentation rate, C-reactive 

protein, haptoglobin, orosomucoid, ceruloplasmin, and 

alpha-1-antitrypsin. 

27 

IV. RESEARCH SUGGESTIONS 

In the opinion of the ad hoc Working Group on Immunocompetence in Space, NASA should plan and conduct a series of 

investigations aimed at settling the question of whether space 

flight induces changes in immune competence. The goal should be 

to characterize the changes in terms of their potential clinical 

and operational significance. Inflight investigations should 

predominate, with primary emphasis on human studies; however, 

inflight animal studies are also justified as a part of such a 

program. Postflight studies are important also, and all studies 

must be compared with ample preflight data. If the suggested 

research demonstrates potentially serious changes in immunocompetence, further attention could then focus upon causes, 

mechanisms, and means of intervention. The suggestions of the 

ad hoc Working Group are divided into four sections: immediate 

research needs, potential research needs, tests and methodology, 

and facilities and equipment. These research needs are derived, 

in part, from the questions raised in the preceding section. 

A. IMMEDIATE RESEARCH NEEDS 

Data from the following types of studies should lead 

to a firm conclusion on whether space flight causes changes in 

immunocompetence that imply potentially serious adverse health 

effects for space crews. The suggestions are presented in 

descending order of approximate priority. 

e Determine inflight immune responses of space crew 

members including antibody production and delayed 

type hypersensitivity reactions to common antigens. (See Section IV-C for suggested methods.) 

postflight from space crews to make lymphokines such 

as interleukin-2, interleukin-3, and gamma-interferon 

and to generate lymphokine receptor such as that for 

interleukin-2. RNA extraction and Northern blots for 

five or six monokines and lymphokines can be done on 

a single frozen cell pellet (Wiskocil et al., 1985). 

For T-lymphocyte transformations, PHA and ConA are 

appropriate nonspecific mitogens; PPD, mumps, streptokinase-streptodornase, tetanus toxoid, and Candida 

albicans are useful specific antigens (Lane et al., 

1986). 

' 

e Study the capacity of activated T-lymphocytes obtained 

e Examine recruitment of human neutrophils and mononuclear 

cells and the release of their lysosomal contents inflight as well as postflight by means of in vivo induction of localized skin inflammation via the Rebuck skin 

window or blister machine techniques (Dale and Wolff, 

1971; Hellum and Solberg, 1977; Rebuck and Crowley, 

29 
1955; Scheja and Forsgren, 1985). The methods are 

essentially innocuous and frequently used in children. 

The resulting minor skin lesions offer a means of 

observing wound healing as well. Examining mouth 

washings for neutrophils is another means of acquiring 

some data on the inflammatory response as it relates to 

gingivitis or other oral lesions (Wright et al., 1986). 

Determine the temporal pattern of changes in key human 

immunologic parameters such as white blood cell count, 

differential count, and blastogenic responsiveness of 

T-lymphocytes. To be adequate, sampling times must 

include preflight baseline values, inflight at 24-48 h, 

mid-mission, and shortly before reentry; postflight 

at 24-48 h, as well as 7, 14, 21, and 30 d. Possibly 

related variables should also be measured in the blood 

specimens for this study including epinephrine, 

cortisol; acute phase reactants (C-reactive protein, 

haptoglobin, ceruloplasmin, orosomucoid, alpha-lantitrypsin) as well as plasma zinc, iron, and copper. 

* Determine the following functional capacities of 

peripheral blood neutrophils and monocytes obtained 

from specimens from space crew personnel at selected 

times postflight including within 24 h of landing, as 

well as 7 and 14 d: chemotactic response, adherence, 

locomotion, phagocytosis, degranulation, bactericidal 

activity, oxidative metabolism, and respiratory burst. 

* Pre- and postflight studies of the uptake of complementaltered red blood cells by the reticuloendothelial 

system should be considered. Macrophage phagocytosis 

can be measured in vivo by the uptake of chromiumtagged, antibody-coated red blood cells by the splenic 

macrophages and the hepatic Kupfer cells. The procedure 

requires a series of blood samplings to estimate 

clearance of the tagged red cells (Frank et al., 1979, 

1983). (e also Section IV-C, Methods.) 

B. RESEARCH NEEDS SHOULD SPACE-RELATED IMMUNOLOGIC CHANGES 

DEMONSTRATE POTENTIALLY UNACCEPTABLE HEALTH RISKS 

Laboratory evidence of impaired immunocompetence is not 

always associated with disease. However, if the results of the 

investigations suggested in Section IV-A should provide convincing evidence that long space missions (arbitrarily defined 

as >30 d) induce potentially unacceptable changes in immunocompetence, studies such as those described below will be 

advisable to determine the causes, mechanisms, and detailed. 

characteristics of the changes and to develop means of intervention. The suggestions are listed roughly in descending order 

of priority . 

30 
0 Determine functional responses of human T-lymphocytes 

activated during space flight by specific and nonspecific antigens in terms of blastogenic transformation 

and ability to produce monokines and lymphokines. 

parameters of neutrophils and monocytes from human 

blood obtained within 24-48 h after landing: 

morphology, motility, spreading ability, cell 

aggregation, adherence, degranulation, and oxidative 

metabolism. Measure the markers for the C3bi receptors 

such as the OKM-1 and LFA-1 antigens in neutrophils from 

crew members who demonstrate postflight neutrophilia. 

0 Examine the following functional and histologic 

0 In vitro studies of the generation of human and animal 

cytotoxic T-cell populations against an appropriate 

battery of allogeneic stimulator cells should be 

conducted in space. The cytotoxic activity of these 

cultures could easily be measured on the appropriate 

radiolabeled cultured target cells such as K562 cells. 

Such studies need appropriate positive and negative 

controls in space and a full replicate of ground-based 

studies (Grabstein, 1980). 

0 Other in vitro flight experiments that would aid in 

characterizing cellular responses to the space flight 

environment should be considered. Examples would 

include changes in in vitro morphogenesis of monocytes 

over a period of 7 d in space and in endothelial cells 

in culture for contact inhibition and the laying down 

of basement membrane. In addition, it would be useful 

to determine the effects of space flight on activated 

cultures of HL6'0 cells in terms of their ability to 

differentiate into mononuclear and polymorphonuclear 

types of cells. Cells could be fixed and stained 

appropriately and culture fluid saved at various times 

of differentiation inflight for subsequent evaluation 

postflight. 

0 Other postflight assays of lymphocytic responses 

that should be considered include: (1) spontaneous 

lymphocyte proliferation in fresh specimens observed 

during the first few hours following venipuncture; 

(2) the response to a soluble antigen such as tetanus 

toxoid; (3) the response to alloantigen; (4) changes 

in patterns of subsets of lymphocytes; (5) numbers and 

functional capacity of natural killer cells; and (6) the 

cytotoxic lymphocyte response, that is, the interaction 

of the cytotoxic T-cell with an appropriate target cell 

(Lane et al., 1986). 

31 
0 Flight experiments with mice or rats should be devised 

to examine the effects of space flight on several 

immunologic parameters including antibody responses to 

a variety of antigens administered immediately before or 

during flight (see Section IV-C for suggested antigens), 

possible changes in the morphology and immunologic 

characteristics of crucial organs and tissues of the 

immune system such as bone marrow, spleen, liver, lymph 

nodes, and organ-related lymphoid tissues of the upper 

and lower respiratory systems, gastrointestinal and 

genitourinary tracts and the skin, and measurement 

of prostaglandins in representative tissues of the 

immune system as well as pituitary gland neuropeptides. 

Acute phase reactants in serum should be measured as 

well (see - p.30 for examples). All such parameters can 

be done with blood and tissues obtained postflight; 

animals preserved postflight would permit an assessment 

of temporal patterns of recovery. Procedural permutations could be added such as administering immunogens 

during flight instead of preflight, and taking specimens 

of body fluids, tissues, and microflora inflight. 

0 A set of measurements should be selected and added 

to NASA's routine pre- and postflight laboratory and 

clinical assessment batteries to develop a data base 

that would aid in evaluating changes in immunocompetence. Candidate measures should include the 

stress hormones, the several immunoglobulins, acute 

phase reactants, serum iron, total iron binding 

capacity, serum zinc, and serum copper, white cell 

count, differential white cell count, and platelets. 

Clinical procedures should include a careful examination 

by a trained expert for gingival inflammation and plaque 

formation (Charon et al., 1985) and a check of the nasal 

and conjunctival mucosae. Any parameter not within 

normal limits should be followed until return to the 

normal range. An expert psychologic or neuropsychiatric 

appraisal of each crew member should be a routine 

postflight procedure as an approach to evaluating stress 

responses. Wherever possible, individual crew members 

should serve as their own controls. (See also Section 

IV-c. ) 

0 Ground-based studies of the effects of various stresses 

on populations of. human lymphocytes and circulating 

hormones should be considered. If the stresses produce 

changes in lymphocytes, follow-up studies could be done 

to determine whether individual stress hormones given in 

doses to reproduce blood concentrations measured during 

stress exposures cause similar responses. Frequency of 

blood sampling should allow for detection of momentary 

32 
peak hormone values. 

planning because of the diversity of stresses that 

could be used, steroid and neural hormones that might 

be released, and attendant difficulties in hormone 

analysis. 

Such studies need very careful 

Details of methodology for the following suggestions 

should be the subject of a separate workshop on the microbiologic 

aspects of space flight: 

0 Crew members who are scheduled for a space mission and 

who have evidence of latent viral infection, such as 

herpes simplex or cytomegalovirus, would be prime 

candidates for some relatively simple virology studies. 

Culturing such individuals for viral shedding before and 

after space flights could provide data on the effects of 

transient decreases in immunocompetence. 

0 Experiments should be designed to acquire data on 

possible changes in the types and virulence of human 

gingival and dental plaque flara during flight as one 

approach toward an explanation of the gingivitis of the 

Skylab astronauts. 

0 The question whether weightlessness induces changes 

in interfaces and interactions among liquids, solids, 

gases, and mucosal surfaces of the small and large 

bowel, urinary, and respiratory tracts and possible 

associated effects such as changes in the microflora 

including overgrowth of certain species or colonization 

of normally sterile sites should be considered. For 

example, quantitation of the numbers and types of 

bacteria present in freshly voided urine; this should 

include cultures of fresh urine samples which could be 

assayed for bacteria and the presence of mucus (glucose 

aminoglycans) that lines the urinary tract. The loss of 

mucus would predispose to bacterial colonization of the 

urinary tract. Studies of this sort could be a part of 

other inflight and postflight human observations and 

animal experiments. 

0 Factors that favor the multiplication and conversion of 

a normally nonpathogenic microbe of the normal human 

microflora to a pathogen during space flight are of 

special interest, especially in the presence of 

partially altered immunocompetence. Data are needed 

for predicting such opportunistic infections inflight 

and postflight in healthy as well as immunocompromised 

crew members. 

33 
C. 

0 There is some evidence of changes in microfloral ecology 

in spacecraft during flight that result in alterations 

of the total array of antigens to which crew members 

are exposed. Data are needed on whether changes such 

as simplification of the flora affect human immunocompetence and, if so, to what degree and by which 

specific microorganisms. 

TESTS AND METHODOLOGIES 

0 The effects of space flight on cell-mediated immunity 

could be tested by administering a battery of ubiquitous 

antigens intradermally several weeks before flight and 

again during or i-mediately postflight. 

0 A booster shot of tetanus toxoid can be given pre- or 

during flight to test the secondary humoral immune 

responsiveness in space to a well-defined recall 

antigen. 

0 A sensitive method of assessing the ability of a host to 

elicit an antigen-specific primary humoral and cellular 

immune response would be to immunize during flight with 

a primary antigen such as keyhole limpet hemocyanin 

(KLH), followed in 2 wk by a booster to test for a 

secondary humoral response. In addition, a skin test 

for delayed-type hypersensitivity may be done to test 

for cell-mediated immunity. This series of procedures 

would require a space flight lasting at least 3 wk. 

Serial blood samples during and after flight would 

permit monitoring of the serologic response to KLH and 

possible changes in immunoglobulin levels. Postflight 

blast transformation of the subjects' T-lymphocytes 

would complete the test package. 

and liver can be estimated by a tracer technique. 

Erythrocytes obtained postflight from individual 

spacesfew members can be coated with IgG, radiolabeled 

with Cr, and then reinfused into the donor. The 

removal of the tagged cells from the circulation can be 

measured conveniently. The rate of clearance is a good 

indicator of macrophage function in vivo in terms of 

phagocytosis or dissociation by the reticuloendothelial 

system. Baseline values should be established by 

preflight estimates in the same individuals (Frank 

et al., 1983). 

0 In vivo phagocytic function of macrophages in the spleen 

34 
0 A convenient technique for estimating the possible 

influence of monocytopenia on the blastogenic 

transformability of T-lymphocytes taken postflight 

from spacecrew members is to add autologous monocytes 

to the test culture and observe whether the decreased 

PHA response becomes normal (Lewis and Robbins, 1970). 

Relatively simple observations of living neutrophils 

are possible during spaceflight such as (1) morphology, 

(2) motility, (3) content of lysosomal granules, (4) 

phagocytosis, and (5) the nitroblue tetrazolium (NBT) 

test and cytochrome C reduction assay for oxidative 

metabolism, Necessary equipment would include microscope, glass slides, simple reagents, and blood samples. 

Some tests performed inflight could be quantitated 

postflight. 

0 

0 Immediately postflight, neutrophils can be tested for 

(1) degranulation (release of lactoferrin and enzymes), 

(2) C3bi receptors using such antigens as OKM-1 and 

LFA-1, (3) phagocytosis, (4) chemotaxis, and (5) 

bactericidal activity. 

0 For ease of handling and analysis, certain well-defined 

tumor cell lines that have some of the properties of 

normal lymphocytes, such as Jurkat cells, are available 

and could be used in in vitro flight tests of lymphocyte 

activation in experiments similar to those of Cogoli and 

Tschopp (19851, This human T-cell tumor line can make 

interleukin-2 in the absence of accessory cells by 

adding phorbol esters and PHA (Weiss and Stobo, 19841, 

Similar studies can also be performed on purified mouse 

T-cells (Malek et al., 19851, Thus, one can distinguish 

the effect of space flight on activation responses of 

cells that do not require cell interaction from those 

that do, such as normal T-lymphocytes, 

0 If NASA concurs in the suggestions for future studies 

of the immunologic aspects of space flight presented 

in this report, it may be useful to devise and adopt 

a protocol for assessing the immunocompetence of spacecrews. From a practical point of view, comprehensive 

plans for immunologic assessment should be based on well 

standardized protocols which should be formulated by a 

committee of experts and should include or exceed stateof-the-art classical testing of patients with clinical 

immunodeficiency disorders. 

35 
D. FACILITIES AND EQUIPMENT 

Scientists who may be interested in participating in 

NASA-sponsored studies in immunology and microbiology should 

be aware of the availability of certain items of Life Sciences 

Laboratory Equipment (LSLE) that have been designed and tested 

for inflight experiments. Some LSLE can be carried in the 

Shuttle spacecraft without need for the Spacelab configuration. 

Examples include a carry-on incubator, which is described in 

Cogoli and Tschopp (19851, and an Animal Exposure Module (AEM) 

for small animals. The AEM is a self-contained unit requiring no 

handling by the crew. More elaborate inflight facilities include 

the Research Animal Holding Facility (RAHF), which is currently 

in development, and the European Space Agency (ESA) Biorack. 

Both units have been designed for use in the Spacelab and offer 

considerable flexibility in experimental procedures. Other 

equipment has been developed and flight tested for small animals 

as well as in vitro experiments in space biology. A primary 

source of information on NASA's facilities and equipment for 

inflight investigations is the Director, Life Sciences Division, 

Headquarters, National Aeronautics and Space Administration, 

Code EB, Washington, DC 20546. 

E. CONCLUDING REMARKS 

In conclusion, the ad hoc Working Group noted that data 

on the immunologic effects of space flight are conflicting. On 

one hand, approximately 200 spacecrew members have participated 

in missions lasting from a few days up to 7 mo without demonstrating overt adverse effects on immunity and host resistance. 

On the other hand, changes in neutrophil populations and inflight 

and postflight changes in T-lymphocyte responsivity to activation 

show that some aspect of space flight clearly alters cells that 

are primarily responsible for providing normal host immunity 

and microbial defenses. 

The ad hoc Working Group reviewed the evidence carefully 

and suggested numerous studies to overcome current gaps in 

knowledge about immunity in space. Despite the sophisticated 

studies that could be attempted, a clear-cut demonstration of 

normal cell-mediated immunity as measured by delayed dermal 

hypersensitivity reactions during and/or postflight along with 

normal inflight humoral responses to a defined antigen would 

alleviate many of the concerns that have been expressed on the 

basis of the current lack of knowledge. 

36 
V. LITERATURE CITED 

Allen, T.R.; Bradburne, A.F.; Stott, E.J.; Goodwin, C.S.; 

Tyrrell, D.A,J, 1973. An outbreak of common colds at an 

Antarctic base after seventeen weeks of complete isolation. 

J. Hyg. (Cambridge) 71:657-667, 

Anderson, D,C.; Schmalstieg, F,C,; Shearer, W,; Becker-Freeman, 

K.; Kohl, S.; Smith, C.W.; Tosi, M.F.; Springer, T. 1985. 

Leukocyte LFA-1, OKM1, p150,95 deficiency syndrome: functional 

and biosynthetic studies of three kindreds. Fed, Proc. Fed. Am. 

SOC. Exp. Biol. 44:2671-2677. 

Angrick, E.J.; Somerson, N.L.; Weiss, H.S, 1974. Oxygen effects 

on mortality of mice infected with Diplococcus pneumoniae. 

Aerospace Med. 45:730-734, 

Anonymous. 1985. Emotion and immunity. Lancet 2:133-134. 

Arnaout, M.A.; Dana, N.; Pitt, J.; Todd, R.F., 111. 1985. 

Deficiency of two human leukocyte surface membrane glycoproteins 

(Mol and LFA-1). Fed. Proc. Fed. Am. SOC. Exp. Biol. 

44~2664-2670. 

Bailey, J.V. 1975. Radiation protection and instrumentation. 

In: Johnston, R,S.; Dietlein, L.F.; Berry, C.A., eds. Biomedical results of Apollo. NASA SP-368. Washington, DC: 

National Aeronautics and Space Administration. 

Balish, E.; Shih, C.-N.; Yale, C.E.; Mandel, A.D. 1977. Effect 

of 30 months in a locked environment on the microbial flora of 

dogs. Aviat. Space Environ. Med. 48:424-431. 

Barone, R.P.; Caren, L.D. 1984. The immune system: effects of 

hypergravity and hypogravity, Aviat. Space Environ. Med. 

55~1063-1068. 

Bartrop, R.W.; Luckhurst, E.; Lazarus, L.; Kiloh, L.G.; Penny, R. 

1977. Depressed lymphocyte function after bereavement. Lancet 

1:834-836. 

Beisel, W.R.; Edelman, R.; Nauss, K.; Suskind, R.M. 1981. 

Single-nutrient effects on immunologic functions. J. Am. Med. 

ASSOC. 245~53-58. 

Benton, E.V.; Almasi, J.; Cassow, R.; Frank, A.; Henke, R.P.; 

Rowe, V.; Parnell, T.A.; Schopper, E. 1984. Radiation 

measurements aboard Spacelab 1. Science 225:224-226. 

Berry, C.A, 1973. The medical legacy of Apollo. Paper 

presented at 21st International Congress of Aviation and Space 

Medicine, Munich, September 17. 

37 
Berry, C.A. 1974. The medical legacy of Apollo. Aerospace Med. 

45~1046-1057. 

Blalock, J.E.; Smith, E.M. 1985. A complete regulatory loop 

between the immune and neuroendocrine systems. Fed. Proc. Fed. 

Am. SOC. Exp. Biol. 44:108-111. 

Bricker, N.S., chairman. 1979. Life beyond the Earth's 

environment: the biology of living organisms in space. Report 

of the Committee on Space Biology and Medicine, Space Science 

Board. Washington, DC: National Academy of Sciences. 

Brockett, R.M.; Ferguson, J.K. 1975. Microbiological sampling 

of the spacecraft atmosphere during a simulated Skylab mission. 

Aviat. Space Environ. Med. 46:30-32. 

Brown, L.R.; Frome, W.J.; Handler, So; Wheatcroft, M.G.; Rider, 

L.J. 1977. Skylab oral health studies. In: Johnston, R.So; 

Dietlein, L.F., eds. Biomedical results from Skylab. NASA 

SP-377. Washington, DC: National Aeronautics and Space 

Administration. p.35-44. 

Caren, L.D.; Mandel, A.D.; Nunes, J.A. 1980. Effect of 

simulated weightlessness on the immune system in rats. Aviat. 

Space Environ. Med. 51:251-255. 

Casarett, G.W. 1969. Pathological changes after protracted 

exposures to low-dose radiation. In: Fry, R.J.M.; Grahn, D.; 

Griem, M.L.; Rust, J.H., eds. Late effects of radiation. New 

York: Van Nostrand Reinhold. p.85-100. 

Chang, K.-J. 1984. Opioid peptides have actions on the immune 

system. Trends Neurosci. 7:234-235, 

Charon, J.A.; Mergenhagen, S.E.; Gallin, J.I. 1985. Gingivitis 

and oral ulceration in patients with neutrophil dysfunction. J. 

Oral Pathol. 14:150-155. 

Christensen, J.M.; Talbot, J.M., editors. 1985. Research 

opportunities in human behavior and performance. Report 

prepared for the National Aeronautics and Space Administration, 

Washington, DC, under Contract No. NASW 3924 by the Life Sciences 

Research Office, Federation of American Societies for Experimental Biology, Bethesda, MD. 73p. Available from: FASEB 

Special Publications, Bethesda, MD. 

Cogen, R.B.; Stevens, AoW., Jr.; Cohen-Cole, S.; Kirk, K.; 

Freeman, A. 1983. Leukocyte function in the etiology of acute 

necrotizing ulcerative gingivitis. J. Periodontol. 54:402-407. 

Cogoli, A. 1981. Hematological and immunological changes during ~ space flight. Acta Astronautica 8:995-1002. 

38 
Cogoli, A,; Tschopp, A. 1985. Lymphocyte reactivity during 

spaceflight. Immunol. Today 6:l-4. 

Cogoli, A.; Tschopp, A.; Fuchs-Bislin, P, 1984. Cell 

sensitivity to gravity. Science 225:228-230. 

Cogoli, A,; Valluchi-Morf, M.; Mueller, M,; Briegleb, W, 1980. 

Effect of hypogravity on human lymphocyte activation. Aviat. 

Space Environ, Med. 51:29-34. 

Dale, D.C.; Wolff, S.M. 1971. Skin window studies of the 

acute inflammatory responses of neutropenic patients, Blood 

38~138-142, 

Dietlein, L.F. 1977. Skylab: a beginning. In: Johnston, 

R.S.; Dietlein, L.F., eds. Biomedical results from Skylab. 

NASA SP-377. Washington, DC: National Aeronautics and Space 

Administration. p.408-414. 

Durnova, G.N.; Kaplansky, A.S.; Portugalov, V.V. 1976, Effect 

of a 22-day space flight on the lymphoid organs of rats. Aviat. 

Space Environ. Med. 47:588-591. 

Ferguson, J.K.; Taylor, G.R.; Mieszkuc, B,J. 1975. 

Microbiological investigations. In: Johnston, R.S.; Dietlein, 

LeF.; Berry, C.A., eds. Biomedical results of Apollo. NASA 

SP-368. Washington, DC: National Aeronautics and Space 

Administration. p,83-104. 

Frank, M.M.; Hamburger, M.I.; Lawley T.J.; Kimberly, R.P.; Plotz, 

P.H, 1979. Defective reticuloendothelial system Fc receptor 

function in systemic lupus erythematosus. New Engl. J. Med, 

300:518-523. 

Frank, M-M.; Lawley, T.J.; Hamburger, M.I.; Brown, E.J. 1983. 

Immunoglobulin G Fc receptor-mediated clearance in autoimmune 

disease. Ann. Intern. Med. 98:206-218. 

Gershwin, M.E.; Beach, R,S.; Hurley, L.S. 1985. Nutrition and 

immunity. New York: Academic Press, pel-417. 

Gillmore, J.D.; Gordon, FOB. 1974. Parabarosis and experimental 

infection, 5. Effect of altered oxygen tension on Coxsackie B-1 

infection in adult mice. Aerospace Med. 45:840-842. 

Giron, D.J.; Pindak, F.F.; Schmidt, J.P. 1967. Effects of 

a space cabin environment on viral infection. Aerospace Med. 

38~832-834. 

Gordon, F.B.; Gillmore, J.D. 1974a, Parabarosis and 

experimental infections, 1. Effect of varying O2 tensions on 

influenza virus infection in mice. Aerospace Med. 45:241-248. 

39 
Gordon, F.B.; Gillmore, J.D, 1974b. Parabarosis and 

experimental infections. 4. Effect of varying 0 tensions on 

Chlamydial infection in mice and cell cultures. zerospace Med. 

45 2 257-262. 

Grabstein, K, 1980, Cell-mediated cytolytic responses. In: 

Mishell, B.B.; Shiigi, S.M., eds, Selected methods in cellular 

immunology. San Francisco: W.H. Freeman and Company, p.124- 

137. 

Guseva, Ye. V.; Tashpulatov, R. Yu. 1979. Effects of 49-day 

space flight on parameters of immunological reactivity and 

protein composition of blood in the crew of Salyut-5. Space 

Biol. Aerospace Med. 13(1):1-7, [Translation of Kosmicheskaya 

Biologiya i Aviakosmicheskaya Meditsina 13(1):3-81. 

Guseva, Ye. V,; Tashpulatov, R. Yu. 1980. Effect of flights 

differing in duration on protein composition of cosmonauts' 

blood. Space Biol, Aerospace Med. 14(1):15-20. [Translation 

of Kosmicheskaya Biologiya i Aviakosmicheskaya Meditsina 

14(1):13-17]. 

Hellum, K.B,; Solberg, C.O. 1977, Human leucocyte migration: 

studies with an improved skin chamber technique. Acta Pathol. 

Microbiol. Scand. Section C. 85:413-423, 

Hordinsky, J.R, 1977. Skylab crew health--crew surgeons' 

reports. In: Johnston, R.S.; Dietlein, L,F., eds. Biomedical 

results from Skylab, NASA SP-377, Washington, DC: National 

Aeronautics and Space Administration. p.30-34. 

Ivanov, A.A.; Shvets, V.N.; Boyko, M.I. 1983. Complement and 

heterophil antibody levels in monkeys during antiorthostatic 

hypokinesia. Space Biol. Med. 17(1):93-95. [Translation 

of Kosmicheskaya Biologiya i Aviakosmicheskaya Meditsina 

17(1):66-67], 

Kimzey, SOL. 1977. Hematology and immunology studies. In: 

Johnston, R.S.; Dietlein, L.F., eds. Biomedical results from 

Skylab. NASA SP-377. Washington, DC: National Aeronautics and 

Space Administration. p.249-283. 

Kimzey, S.L.; Fischer, C.L.; Johnson, P.C.; Ritzmann, S.E.; 

Mengel, C.E. 1975a. Hematology and immunology studies, In: 

Johnston, R.S.; Dietlein, L.F.; Berry, C.A., eds. Biomedical 

results of Apollo. NASA SP-368, Washington, DC: National 

Aeronautics and Space Administration. p.197-226. 

Kimzey, S.L.; Ritzmann, S.E.; Mengel, C.E.; Fischer, C.L. 

1975b. Skylab experiment results: hematology studies, 

Acta Astronautica 2:141-154. 

40 
Konstantinova, I.V.; Antropova, Ye, N,; Legen'kov, V.1,; 

Zazhirey, V.D, 1973. Study of reactivity of blood lymphoid 

cells in crew members of the Soyuz-6, Soyuz-7 and Soyuz-8 

spaceships before and after flight. Space Biol. Med. 

7(6):48-55. [Translation of Kosmicheskaya Biologiya 

i Aviakosmicheskaya Meditsina 7(6):35-401. 

Konstantinova, I.V.; Nefedov, Yu. G-; Yeremin, A.V.; Drozdova, 

V.I.; Skryabin, A.S.; Guseva, D.A.; Mukhina, N.N. 1978. 

Immunological reactivity and prediction of allergic complications 

in the crew of the second expedition of Salyut-4. 

Med. 12(2):16-21. [Translation of Kosmicheskaya Biologiya i 

Aviakosmicheskaya Meditsina 12(2):15-19]. 

Space Biol. 

Lane, H.C.; Whalen, G.; Fauci, A.S. 119861. - In vitro evaluation 

of human lymphocyte function. In: Weir, D.M.; Herzenberg, L.A.; 

Blackwell, C.C.; Herzenberg, L.A., eds. Handbook of experimental 

immunology. 4th ed. Edinburgii: Blackwell Scientific Publishers. In press. 

Legen'kov, V.I.; Kiselev, R.K.; Gudim, V.I.; Moskaleva, G.P. 

1977. Changes in peripheral blood of crew members of the 

Salyut-4 orbital station. Space Biol. Med. 11(6):1-12. 

[Translation of Kosmicheskaya Biologiya i Aviakosmicheskaya 

Meditsina 11(6):3-12]. 

Lewis, W.R.; Robbins, J.H. 1970. Effect of glass-adherent 

cells on the blastogenic response of purified lymphocytes to 

phytohemagglutinin. Exp. Cell Res. 61:153-158. 

Luckey, T.D. 1966. Potential microbic shock in manned aerospace 

systems. Aerospace Med. 37:1223-1228. 

Malek, T.R.; Schmidt, J.A.; Shevach, E.M. 1985. The murine IL 2 

receptor. 111. Cellular requirements for the induction of IL 2 

receptor expression on T cell subpopulations. J. Immunol. 

134~2405-2413. 

Mandel, A.D.; Balish, E. 1977. Effect of space flight 

on cell-mediated immunity. Aviat. Space Environ. Med. 

48:1051-1057. 

Mikhaylovskiy, G.P.; Dobronravova, N.N.; Kozar, M.I.; Korotayev, 

M.M.; Tsiganova, N.I.; Shilov, V.M.; Yakovleva, I. Ya. 1967. 

Variation in overall body tolerance during a 62-day exposure to 

hypokinesia and acceleration. Space Biol. Med. 1(6):101-108. 

[Translation of Kosmicheskaya Biologiya i Aviakosmicheskaya 

Meditsina 1(6):66-70]. 

Morey, E.R. 1979. Spaceflight and bone turnover: correlation 

with a new rat model of weightlessness. Bioscience 29:168-172. 

41 
National Research Council, Committee on Space Medicine. 1970. 

Radiation protection guides and constraints for space mission and 

vehicle design studies involving nuclear systems. Washington, 

DC: National Academy of Sciences. 

National Research Council, Food and Nutrition Board. 1980. 

Recommended dietary allowances. 9th rev, ed. Washington, DC: 

National Academy of Sciences. 185~. 

Nicogossian, A.E.; Parker, J.F., Jr. 1982. Space physiology and 

medicine. NASA SP-447. Washington, DC: National Aeronautics 

and Space Administration, 324p. 

Park, S.K.; Brody, J.1.; Wallace, H.A.; Blakemore, W.S. 1971. 

Immunosuppressive effect of surgery. Lancet 1:53-55. 

Parkinson, A.J.; Muchmore, H.G.; McConnell, T.A.; Scott, L.V.; 

Miles, J.A.R. 1980. Serologic evidence for parainfluenzavirus 

infection during isolation at South Pole Station, Antarctica. 

Am. J. Epidemiol. 112:334-340. 

Pestov, I.D.; Geratewohl, S.J. 1975. Weightlessness. In: 

Calvin, M.; Gazenko, O.G., general eds. Foundations of space 

biology and medicine. Vol. 2. Book 1. Washington, DC: 

National Aeronautics and Space Administration. p.317, 327, 330. 

Pierson, D.L. 1983. Medical microbiology of crew members and 

spacecraft during OFT. In: Pool, S.L.; Johnson, P.C., Jr:; 

Mason, J.A., eds. Shuttle medical report: summary of medical 

results from STS-1, STS-2, STS-3, and STS-4. NASA TM 58252. 

Johnson Space Center: National Aeronautics and Space 

Administration. p.49-52. 

Plotnikoff, N.P.; Murgo, A.J. 1985. Enkephalins-endorphins: 

stress and the immune system. Fed. Proc. Fed, Am. SOC. Exp. 

Biol. 44:91. 

Poteliakhoff, A. 1985. Emotion and immunity. Lancet 2:327. 

Rebuck, J.W.; Crowley, J.H. 1955. A method of studying 

leukocytic functions in vivo. Ann. N.Y. Acad. Sci. 59:757-793. 

Riley, V. 1981. Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 212:llOO-1109. 

Ritzmann, S.E.; Levin, W,C. 1973. Investigation of man's immune 

system (M 112), part B. Skylab Medical Experiments Altitude 

Test. Johnson Space Center: National Aeronautics and Space 

Administration. 

Rose, R.M. 1980. Endocrine responses to stressful psychological 

events. Psychiatr. Clin. North Am. 3:251-276. 

42 
Sawyer, R,; Sommerville, R.G. 1966. An outbreak of Mycoplasma 

pneumoniae infection in a nuclear submarine. J. Am. Med. Assoc. 

195: 958-959. 

Scheja, A.; Forsgren, A, 1985. A skin chamber technique for 

leukocyte migration studies: description and reproducibility. 

Acta Pathol. Microbiol. Immunol. Scand, Section C. 93:25-30. 

Seed, T.M.; Fritz, T.E.; Tolle, D.V.; Poole, C.M.; Lombard, L.S.; 

Doyle, D.E.; Kaspar, L.V.; Cullen, S.M.; Carnes, BOA. 1984. 

Survival patterns and hemopathological responses of dogs under 

continuous gamma irradiation. In: Broerse, J.J.; MacVittie, 

T.J., eds. Responses of different species to total body 

irradiation. The Hague: Martinus Nijhoff Publishers. 

p.137-159. 

Simmonds, R.C.; Wrenn, R.T.; Heimpel, A.M.; Taylor, G.R. 1974. 

Postflight analysis of Bacillus thuringiensis organisms exposed 

to spaceflight conditions on Apollo 16. Aerospace Med. 45:1244- 

1247. 

Sonnenfeld, G.; Morey, E.R.; Williams, J.A.; Mandel, A.D. 1982. 

Effects of a simulated weightlessness model on the production of 

rat interferon. J. Interferon Res. 2:467-470. 

Spector, N.H. 1983. Anatomic and physiologic connections 

between the central nervous and the immune systems (Neuroimmunomodulation). In: Fabris, N.; Garaci, E.; Hadden, J.; Mitchison, 

N.A., eds. Immunoregulation. New York: Plenum Publishing 

Corporation. 

Springer, T.A. 1985. The LFA-1, Mac-1 glycoprotein family and 

its deficiency in an inherited disease. Fed. Proc. Fed. Am. SOC. 

Exp. Biol, 44:2660-2663. 

Talas, M.; Batkai, L.; Stoger, I.; Nagy, K.; Hiros, L,; 

Konstantinova, I.; Rykova, M.; Mozgovaya, I.; Guseva, 0.; 

Kozharinov, V, 1983. Results of space experiment program 

"interferon". Acta Microbiol, Hungarica 30(1):53-61. 

Tansey, W.A.; Wilson, J.M.; Schaefer, K.E, 1979. Analysis of 

health data from 10 years of Polaris submarine patrols. Undersea 

Biomed. Res. Submarine Suppl.:S217-S246. 

Taylor, G.R, 1974. Recovery of medically important microorganisms from Apollo astronauts. Aerospace Med. 45:824-828. 

Taylor, G.R.; Dardano, J.R. 1983. Human cellular immune 

responsiveness following space flight. Aviat. Space Environ. 

Med. 54(Suppl. 1):S55-S59. 

43 
Taylor, G.R.; Graves, R.C.; Brockett, R.M.; Ferguson, J.K.; 

Mieszkuc, B.J. 1977. Skylab environmental and crew microbiology. In: Johnston, R.S.; Dietlein, L.F., eds. Biomedical 

results from Skylab. NASA SP-377. Washington, DC: National 

Aeronautics and Space Administration. p.53-63. 

Unanue, E.R. 1981. The regulatory role of macrophages in 

antigenic stimulation. 11. Symbiotic relationships between 

lymphocytes and macrophages. Adv. Immunol. 31:l-136. 

Vorobyev, E.I.; Gazenko, O.G.; Genin, A.M.; Egorov, A.D. 1983. 

Medical results of Salyut-6 manned space flights. Aviat. Space 

Environ. Med. 54(Suppl. 1):S31-S40. 

Vorobyev, Ye. I.; Gazenko, O.G.; Genin, A.M.; Gurovskiy, N.N.; 

Yegorov, A.D.; Nefedov, Yu. G. 1984. Main results of medical 

studies on Salyut-6-Soyuz program. Space Biol. Med. 18(2): 

27-31. [Translation of Kosmicheskaya Biologiya i Aviakosmicheskaya Meditsina 18(2):22-251. 

Voss, E.W., Jr. 1984. Prolonged weightlessness and humoral 

immunity. Science 225:214-215. 

Watkins, H.M.S. 1970. Epidemiologic investigations in Polaris 

submarines. In: Silver, I.H., ed. Aerobiology. New York: 

Academic Press. p.9-53. 

Weiss, A.; Stobo, J. 1984. Requirement for the coexpression of 

T3 and the T cell antigen receptor on a malignant human T cell 

line. J. Exp. Med. 160:1284-1299. 

Whedon, G.D., chairman. 1978. Future directions for the life 

sciences in NASA. A report of the Life Sciences Advisory 

Committee of the NASA Advisory Council. Washington, DC: 

National Aeronautics and Space Administration. 44p. 

Wiskocil, R.; Weiss, A.; Imboden, J.; Kamin-Lewis, R.; Stobo, J. 

1985. Activation of a human T cell line: a two-stimulus 

requirement in the pretranslational events involved in the 

coordinate expression of interleukin-2 and y-interferon genes. 

J. Immunol. 134:1599-1603. 

Wright, D.G.; Meierovics, A.I.; Foxley, J.M. [1986]. Assessing 

the delivery of neutrophils to tissues in neutropenia. Blood 

In press. 

Yegorov, A.D. 1979. Results of medical research during the 

175-day flight of the third main crew on the Salyut-6 and Soyuz 

complex. Academy of Sciences, USSR, Ministry of Public Health, 

Institute of Biomedical Problems, Moscow. NASA TM-76014. 

Washington, DC: National Aeronautics and Space Administration. 

44 
Yegorov, A.D. 1980. Results of medical research studies during 

long-term manned flights on the orbital Salyut-6 and Soyuz 

complex. 

Soviet-American Working Group on Space Biology and Medicine, 

Moscow. NASA TM-76450. Washington, DC: National Aeronautics 

and Space Administration. 

Presented during the 11th meeting of the Joint 

45 

A. 

VI. STUDY PARTICIPANTS 

ATTENDEES, ad hoc MEETING, July 25-26, 1985 

CO-CHAIRPERSONS 

Kenneth D. Fisher, Ph.D. John M. Talbot, M.D. 

Director Senior Medical Consultant 

Life Sciences Research Office Life Sciences Research Office 

Federation of American Societies Federation of American Societies 

9650 Rockville Pike 9650 Rockville Pike 

Bethesda, Maryland 20814 Bethesda, Maryland 20814 

for Experimental Biology for Experimental Biology 

PARTICIPANTS 

Edward Balish, Ph,D. 

Professor, Departments of 

Surgery and Medical 

Microbiology 

University of Wisconsin 

Medical School, 4638 MSC 

1300 University Avenue 

Madison, Wisconsin 53706 

William R. Beisel, M.D. 

The Johns Hopkins School of 

Hygiene and Public Health 

615 North Wolfe Street 

Baltimore, Maryland 21205 

Zanvil A. Cohn, M.D. 

Professor and Senior Physician 

Rockefeller University 

1230 York Avenue 

New York, New York 10021 

Riley D. Housewright, Ph,D, 

Consultant in Microbiology 

147 Fairview Avenue 

Frederick, Maryland 21701 

H. Clifford Lane, M.D. 

Senior Investigator, Laboratory 

of Immunoregulation, and ' 

Deputy Clinical Director, NIAID 

Building 10, Room 11B13 

National Institutes of Health 

Bethesda, Maryland 20205 

Ethan M. Shevach, M,D. 

Senior Investigator, 

Laboratory of Immunology 

Building 10, Room 11N315 

NIAID 

National Institutes of Health 

Bethesda, Maryland 20205 

Eric M. Smith, Ph.D. 

John I. Gallin, M.D. Associate Professor 

Director, Intramural Research Department of Microbiology 

WIAID Branch 

National Institutes of Health Galveston, Texas 77550 

Bethesda, Maryland 20205 

Program University of Texas Medical 

47 P 
B. NATIONAL AERONAUTICS AND SPACE ADMINISTRATION 

Henry Bielstein, M.D. Arnauld Nicogossian, M.D. 

Manager, Operational Medicine Director, Life Sciences Division 

Life Sciences Division, EBM NASA Headquarters 

NASA Headquarters 600 Independence Avenue, S.W. 

600 Independence Avenue, S.W. Washington, D.C. 20546 

Washington, D.C. 20546 

Philip C. Johnson, Jr., M.D. Gerald R. Taylor, Ph.D. 

Medical Research Branch 

NASA Johnson Space Center Laboratory Mail Code SD 

Houston, Texas 77058 NASA Johnson Space Center 

Chief, Cell Image Analysis 

Biomedical Research Branch - SD3 

Houston, Texas 77058 

OTHER INVITEES 

Joel I. Leonard, Ph.D. 

MATSCO/General E,lectric 

600 Maryland Avenue, S.W. 

Washington, D.C. 20024 

C. LIFE SCIENCES RESEARCH OFFICE STAFF 

Philip L. Altman, M.S. 

Senior Staff Scientist 

Sue Ann Anderson, Ph.D. 

Senior Staff Scientist 

Harolyn Cohen 

Secretary 

Gloria Jean Cole 

Secretary 

Beverly Lea 

Literature Retrieval/ 

Technical Report Specialist 

Judith F. Miller 

Administrative Assistant 

Stephen Simpson 

Literature Technical Assistant 

Joy Ann Williams 

Secretary 

48