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Psychosomatic Medicine 63:886-890 (2001)
© 2001 American Psychosomatic Society

SPECIAL ISSUE: OUTERSPACE RESEARCH

Peripheral Leukocyte Subpopulations and Catecholamine Levels in Astronauts as a Function of Mission Duration

Paul J. Mills, PhD, Janice V. Meck, PhD, Wendy W. Waters, PhD, Dominick D’Aunno, MD and Michael G. Ziegler, MD

From the Departments of Psychiatry (P.J.M.) and Medicine (M.G.Z.), University of California, San Diego, La Jolla, CA; the Cardiovascular Laboratory (J.M.), Johnson Space Center, Houston, TX; and the National Space Biomedical Research Institute (W.W.W., D.D.), Baylor College of Medicine, Houston, TX.

Address reprint requests to: Paul J. Mills, PhD, UCSD Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-0804. Email: pmills{at}ucsd.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: The objective of this study was to determine the effects of spaceflight duration on immune cells and their relationship to catecholamine levels.

METHODS: Eleven astronauts who flew aboard five different US Space Shuttle flights ranging in duration from 4 to 16 days were studied before launch and after landing.

RESULTS: Consistent with prior studies, spaceflight was associated with a significant increase in the number of circulating white blood cells (p < .01), including neutrophils (p < .01), monocytes (p < .05), CD3+CD4+ T-helper cells (p < .05), and CD19+ B cells (p < .01). In contrast, the number of CD3-CD16+56+ natural killer cells was decreased (p < .01). Plasma norepinephrine levels were increased at landing (p < .01) and were significantly correlated with the number of white blood cells (p < .01), neutrophils (p < .01), monocytes (p < .01), and B cells (p < .01). Astronauts who were in space for approximately 1 week showed a significantly larger increase on landing in plasma norepinephrine (p = .02) and epinephrine (p = .03) levels, as well as number of circulating CD3+CD4+ T-helper cells (p < .05) and CD3+CD8+ T-cytotoxic cells (p < .05) as compared with astronauts in space for approximately 2 weeks.

CONCLUSIONS: The data suggest that the stress of spaceflight and landing may lead to a sympathetic nervous system–mediated redistribution of circulating leukocytes, an effect potentially attenuated after longer missions.

Key Words: spaceflight, • leukocytes, • lymphocytes, • catecholamines, • stress.

Abbreviations: NK = natural killer (cells);; SNS = sympathetic nervous system;; WBC = white blood cells.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Numerous studies document the effects of spaceflight on peripheral leukocyte subpopulations (1–4). Typical changes include a near doubling of the number of circulating granulocytes, a more modest increase in the number of monocytes, and a decrease in the number of eosinophils on landing as compared with before launch (see Ref. 3 for review). The numbers of NK cells (CD3-CD16+ or CD56+) and T-cytotoxic cells (CD3+CD8+) are typically decreased, with less consistent effects being reported for T-helper (CD3+CD4+) and B cells (CD19+) (1, 2, 4). These changes in leukocytes, particularly the T lymphocytes, have been associated with potentially important clinical effects, including depressed in vitro mitogen-induced T-cell activation and reduced delayed-type hypersensitivity to antigens (4, 5). Interestingly, these effects on leukocytes may vary as a function of mission duration. A prior study showed that the number of circulating monocytes is increased after missions of 4 to 5 days’ duration yet decreased after missions lasting 6 to 8 days or longer (3).

These observations have raised questions of whether the changes in leukocyte subpopulations and immune function seen after spaceflight are the result of the effects of microgravity and/or the effects of the significant stress associated with launch and landing (3, 6, 7). Regarding the former, the development of new devices, such as the Cell-Mediated Immunity System and the Whole Blood–Staining Device, have enabled direct in-flight testing of the effects of microgravity on the immune system (3, 8). The Cell-Mediated Immunity System, for example, has been used to show that delayed-type hypersensitivity to antigens is reduced in-flight by day 4 of a mission and may be maximally depressed by day 10 (3).

Regarding the latter, psychological and physiological stressors are known to result in a significant redistribution of peripheral leukocyte populations through activation of the sympathetic nervous (SNS) system and/or the hypothalamic-pituitary-adrenal axis (9–11). Given the stressful nature of launch and landing (6, 7), studies have examined whether the SNS and hypothalamic-pituitary-adrenal axis are activated after spaceflight. Studies generally show no change in plasma cortisol levels after spaceflight (1, 2, 12). In contrast, plasma catecholamines are elevated after spaceflight (13–15); however, few studies have examined the potential relationship between changes in catecholamines and changes in leukocyte populations.

This study examined the effects of spaceflight on leukocyte subpopulations and their potential association with changes in catecholamine levels. Leukocyte subsets and plasma norepinephrine and epinephrine levels were gathered before and after landing in astronauts who flew aboard US Space Shuttle flights of different durations.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Eleven astronauts who flew aboard five different US Space Shuttle flights between 1997 and 2000 were studied. The durations of the missions ranged from 4 to 16 days. Studies were conducted 10 days before launch (L-10), on landing day (R+0), and 2 to 4 days after landing (R+2/4). On each test day, subjects had abstained from caffeine, alcohol, and medications for the preceding 12 hours; had not eaten a heavy meal within 4 hours; and had not exercised maximally within 24 hours. An intravenous catheter was inserted into an antecubital vein. After a 20-minute supine rest period, blood samples were drawn for flow cytometry and catecholamine determinations. On landing day (R+0), blood samples were drawn on average 31/2 hours (range, 21/2–5 hours) after the actual landing of the shuttle. Written, informed consent was obtained for all subjects. The protocol was approved by the Johnson Space Center Institutional Review Board.

Flow cytometry (FACSCalibur, Becton-Dickinson, San Jose, CA) using CellQuest software was used to quantify leukocyte populations (16, 17). Whole blood was preserved with ethylenediaminetetraacetic acid and maintained at room temperature (23°C). Blood was processed within 24 hours of collection, and whole blood was stained with monoclonal antibodies conjugated to various fluorochromes. The lysing reagent was FACS Brand Lysing Solution (Becton-Dickinson), which results in a simultaneous lysis of red blood cells and partial fixation of leukocytes. Positive four-color staining was used with monoclonal antibodies conjugated to either fluorescein isothiocyanate, phycoerythrin, peridinin chlorophyll protein, or allophycocyanin (Becton-Dickinson and PharMingen, San Diego, CA). The fluorescence compensation was performed using CaliBRITE beads (Becton-Dickinson) and FACSComp software. Optimal amounts of antibodies were used, and 8000 to 15,000 events were analyzed per tube. Isotypic controls were used for each assay to determine nonspecific staining. Phenotypes were expressed as the percentages of total cells analyzed by flow cytometry.

Blood samples for catecholamines were preserved with ethylenediaminetetraacetic acid, placed on ice, and separated in a refrigerated centrifuge, and the plasma was stored at -80°C until assay. Epinephrine and norepinephrine were determined by radioenzymatic assay (18). Data were analyzed by repeated-measures analysis of variance and correlation analysis (SPSS Statistical Software).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Consistent with prior studies, after landing (R+0), as compared with before launch (L-10), there was a significant increase in the number of WBCs (F = 31, p < .01), neutrophils (F = 23, p < .01), monocytes (F = 13.0, p < .01), CD3+CD4+ T-helper cells (F = 5.8, p < .05), and CD19+ B cells (F = 16.5, p < .01) (Table 1). The number of CD3-CD16+56+ NK cells was decreased (F = 16, p < .01). At R+2/4, with the exception of eosinophils, which were elevated significantly (F = 5.1, p < .05), cell populations were no longer significantly different from cell populations at L-10. There were no significant differences after landing in the total number of mixed lymphocytes or in the number of CD3+CD8+ T-cytotoxic cells (Figure 1).


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  		Table 1. Effects of Spaceflight on Circulating Leukocytesa According to Flight Duration
 


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  		Fig. 1. Percentage of change in number of circulating leukocytes and levels of catecholamines among 11 astronauts after landing (R+0) as compared with preflight (L-10) values. After landing, the number of neutrophils (Neu), monocytes (Mon), CD3+CD4+ T-helper cells (CD4), CD19+ B cells (CD19), and plasma norepinephrine (NE) levels were significantly elevated, whereas the number of NK cells was significantly decreased (p values < .05). Mixed lymphocytes (Lym), eosinophils (Eos), CD3+CD8+ T-cytotoxic cells (CD8), and plasma epinephrine (Epi) were not significantly changed.

 
Plasma norepinephrine levels were significantly increased on landing (F = 17, p = .001); epinephrine levels were increased but not significantly. On landing day norepinephrine was significantly correlated with WBCs (r = 0.85, p < .01), neutrophils (r = 0.72, p < .01), monocytes (r = 0.74, p < .01), and B cells (r = 0.77, p < .01), whereas epinephrine was significantly correlated with WBCs (r = 0.61, p < .05), lymphocytes (r = 0.62, p < .05), monocytes (r = 0.74, p < .01), and B cells (r = 0.67, p < .05).

Given a prior study showing that a mission duration of less than approximately 1 week vs. greater than 1 week differentially affected monocytes on landing (3), we also examined the data by grouping astronauts according to mission duration. Five astronauts from two missions of 1 week or shorter (mission duration of 4–7 days) were grouped together, and six astronauts from three missions of greater than 1 week (mission duration of 11–16 days) were grouped together. Among the 11 astronauts, 4 of the 6 in the longer duration group and 3 of the 5 in the shorter duration group had flown on prior shuttle missions.

Astronauts who were in space for 4 to 7 days showed a significantly greater increase in norepinephrine (approximately 3-fold; F = 8.1, p = .02) and epinephrine (approximately 10-fold; F = 6.5, p = .031) after landing as compared with those in space for 11 to 16 days (Figure 2). Catecholamine values at R+2/4 were not significantly different from values at L-10. Astronauts in the shorter duration group also showed a significantly greater increase in the number of CD3+CD4+ T-helper cells that remained elevated at R+2/4 (F = 5.7, p < .05). CD3+CD8+ T-cytotoxic cells also were increased in the shorter duration group but were decreased in the longer duration group (F = 5.5, p < .05). The increase in the number of total WBCs was marginally greater in the shorter duration group (F = 4.2, p = .07) (Table 1).



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  		Fig. 2. Plasma norepinephrine and epinephrine levels at 10 days before flight (L-10), on landing day (R+0), and 2 to 4 days after landing (R+2/4) in two groups of astronauts differentiated according to mission duration. Astronauts in space for 4 to 7 days showed a significantly greater increase in norepinephrine (p = .02) and epinephrine (p = .03) after landing than those in space for 11 to 16 days.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
Consistent with prior studies, neutrophils, monocytes, T cells, and B cells were elevated on landing, whereas NK cells were decreased. Plasma norepinephrine levels were elevated and correlated with leukocytes after landing. Both norepinephrine and epinephrine levels were increased to a greater extent in astronauts who were in space for shorter missions, as were T-cell subsets. In addition, the total number of WBCs was elevated to a greater degree in astronauts who were in space for fewer days, but this difference was not statistically significant, perhaps because of the relatively small sample size, a limitation of this study that must be noted. With the exception of T-helper cells and eosinophils, immune cell counts and catecholamine levels returned to near prelaunch values 2 to 4 days after landing.

Prior studies have reported elevated supine catecholamine levels after spaceflight (14, 15, 19). The first 3 days of spaceflight are associated with fluid loss, and this alone might elicit SNS activation. However, SNS activation on landing can diminish considerably with very long duration spaceflight (see Ref. 20, in this issue). We examined whether mission duration might differentially affect the SNS by grouping astronauts into two different flight duration groups in a manner similar to that used in a prior study examining monocytes (3). Our findings suggest that diminished SNS activation on landing day may have started as early as 11 days into the flight. Despite our small sample size, there were significant differences in norepinephrine and epinephrine levels and T-cell subsets after landing between astronauts who were in space for 4 to 7 days and those who were in space for 11 to 16 days. Studies using 6 degrees of head-down bed rest, a ground-based analog of spaceflight, indicate a similar progressive decrease in catecholamine levels with increasing duration of head-down tilt from 0 to 7 to 14 days (21). It would be interesting for future studies to examine the effects of spaceflight duration on the SNS and indices of functional immunity, in addition to the enumerative measures examined in this study.

The relationship between elevated catecholamine levels and elevated leukocyte populations is consistent with findings in the general psychoneuroimmunology literature, which show that acute SNS activation leads to a catecholamine-mediated leukocytosis (22, 23). The phenomenon is mediated, in part, by ß2-adrenergic receptors expressed on leukocytes (24, 25). The spaceflight-associated decrease in NK cells, however, is in the opposite direction of findings of a robust increase in the number of circulating NK cells (and T cells) after acute SNS activation (22, 23). NK and T cells often show a "rebound" effect 1 to 2 hours after acute SNS activation, dipping below initial baseline levels (23, 26). Given that blood was sampled 21/2 to 5 hours after landing, it could be that the reduced number of NK cells after landing was the result of a rebound effect. However, this is unlikely because only NK cells were reduced below preflight values, whereas T cells and B cells were elevated. The decrement in NK cells more closely resembles effects seen in the face of more chronic stressors (27, 28). NK cell values had still not returned to preflight levels 2 to 4 days after landing. This reduction in NK cells after spaceflight has been associated with reduced NK function, including cytokine production (29).

In summary, compared with prelaunch, after landing astronauts showed an elevation in the number of circulating leukocytes that correlated with elevated catecholamine levels. Astronauts who spent more time in space showed lower catecholamine levels after landing as well as a corresponding lower number of circulating T cells. As a result of reduced SNS activation, catecholamine-mediated leukocyte trafficking may diminish with a longer duration of spaceflight. Given prior studies showing reduced T cell and NK cell function after spaceflight (4, 5, 29), the effects of prolonged spaceflight on the SNS may have long-term clinical relevance.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
The authors are grateful to Christy J. Perez and Brian Kennedy, PhD, for technical support and to Eileen F. Bessent and Neal Sekiya of the Immunogenetics Laboratory, San Diego Veterans Affairs Medical Center, La Jolla, CA. This work was supported by Grants MO1RR00827 (M.G.Z.) and HL57265 (P.J.M.) from the National Institutes of Health and Grants NCC9105 (P.J.M.) and 96-OLMSA-01-051 (J.V.M.) from the National Aeronautics and Space Administration.

Received for publication September 12, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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