EXPERIMENT RECORD N° 9516
IMMUNO 2 - Consequences of Stress Challenges on stress response systems and Immunity in Space: a multidisciplinary approach
  1. 2015 • ISS Increments 43-44
  2. 2015 • ISS Increments 45-46
  3. 2016 • ISS Increments 47-48
  4. 2016 • ISS Increments 49-50
  5. 2017 • ISS Increments 51-52
  6. 2018 • ISS "Horizons" - long-duration mission
  7. 2018 • ISS Increments 57-58
  8. 2019 • ISS Increments 59-60
  9. 2019 • ISS Increments 61-62
Life Sciences:
  • Human Physiology
  • Immunology and Haematology
  • Medicine/Health
Inês Antunes
ines.antunes@esa.int
A. Chouker (1), S. Baatout (2), M. Morrels (2), R. Quintens (2), B. Crucian (3), C. Sams (3), D. De Quervain (4), M. Feuerecker (1), I. Kaufmann (1), G. Schelling (1), D. Hauer (1), M. Hörl (1), S. Matzel (1), J.I. Pagel (1), N. Montano (5), E. Tobaldini (5), B. Morukov (6), I. Nichiporuk (6), M. Rykova (6), V. Gushin (6), S. Praun (7), B. Roozendaal (8), M. Thiel (9), P. Campolongo (10)
(1)  
Ludwig-Maximilians-University of Munich
Hospital of the University of Munich
Department of Anaesthesiology
Marchioninistrasse 15
81377 München
GERMANY
Tel:  
+49(0)89.7095.6422
Fax:  
+49(0)89.7095.8886
e-mail:  
alexander.chouker@med.uni-muenchen.de
matthias.feuerecker@med.uni-muenchen.de
(2)  
SCK - CEN
Belgian Nuclear Research Centre
Lab of Molecular & Cellular Biology
Boeretang 200
2400 Mol
BELGIUM
e-mail:  
sbaatout@SCKCEN.BE
mmoreels@SCKCEN.BE
(3)  
NASA
JSC - Johnson Space Center
2101 Nasa Pkwy #1
Houston, TX 77058
USA
e-mail:  
brian.crucian-1@nasa.gov
clarence.sams-1@nasa.gov
(4)  
University of Basel
Departments of Medicine & Psychology
SWITZERLAND
(5)  
University of Milan
Cardiovascular Neuroscience Lab
Milano
ITALY
(6)  
IBMP - Institute for Biomedical Problems
State Research Center of The Russian Federation
Khoroshevskoye Shosse 76A
MOSCOW 123007
RUSSIA
Tel:  
+7.499.195.04.63
Fax:  
+7.499.195.22.53
e-mail:  
morukov@imbp.ru
(7)  
University Medical Center Groningen
Institute for Neuroscience
THE NETHERLANDS
(8)  
Institute for Neuroscience
University Medical Center Groningen
THE NETHERLANDS
(9)  
Department of Anaesthesiologyand Intensive Care
University of Heidelberg-Mannheim
Im Neuenheimer Feld 100
69120 Heidelberg
GERMANY
e-mail:  
manfred.thiel@umm.de
(10)  
University La Sapienza
Faculty of Pharmacy and Medicine
Department of Physiology and Pharmacology
Piazzale Aldo Moro 5
00185 Rome
ITALY
BACKGROUND
Space flight conditions affect human health due to complex environmental challenges (“stressors”) which might be most pronounced for extended periods during interplanetary missions. Stress is a constellation of events, beginning with a stimulus (stressor) that precipitates a reaction in the biological system that subsequently activates physiologic sub-systems in the body (stress responses). Stress has long been suspected of playing a role in the etiology of many diseases, and numerous studies have shown that stress can be immunosuppressive and hence may be detrimental to health. Stressful conditions of psychological or physical nature can activate and/or paralyse human innate or specific immunity, respectively, as been demonstrated by our group, e.g.in the course of long-term confinement, stay for 6 months on the International Space Station (ISS), in the Antarctic environment as well as under clinical and experimental conditions.

Because the immune system is crucial for the humans´ body homeostasis and the capability to cope with infectious challenges, immune dysfunction may endanger successful mission accomplishment and is considered to be a space mission relevant topic. This scientific proposal in response to the ILSRA 2009 Call is of prime scientific importance to our research team, as no study conditions of that kind are available in simulated conditions here on Earth.

SPECIFIC GOALS and OBJECTIVES
1.) Assessment of the consequences of stress due to life in Space at μG with increased radiation including sleep alterations, back pain, moderate sleep hypoxia, mood and psychic stress on immunity and the autonomic nervous system (ANS), glucocorticoids (GC), the endocannabinoid (ECS) and the purinergic (PS) stress-response systems.
2.) Association of alterations in immunity and change in the ANS, GC, ECS and PC stress-response systems and due to stress in space with alterations in cognitive and emotional functions, (epi)genetic influence and brain morphology.
Justification for Need of Space Experiment
IMMUNO-2 is an integrative study protocol to provide a more holistic approach to become more conscious of and to increase the knowledge of the complex physiological adaptation of humans during long-term space missions. Adequate function of the human organisms in space is challenged by psychological/biological (e.g., confinement, sleep, pain) and physical stress factors (e.g., μG, variable oxygenation status, radiation). As a result, the immune system is targeted by a multitude of hormones, hormone-like substances as well as radiation effects, leading altogether to an imbalance of immune functions, which can result in diseases. Further, confinement and other stressors can affect cognitive and emotional functions and may even cause affective problems, which, in turn, can negatively impact immunity. Moreover, in a multi- directional way, also infections and inflammation are stress events that interfere with other physiological
systems as described above.

The outcome of this study, due to its multidisciplinary and holistic approach, will be of importance not only in the light of long duration (interplanetary) space missions. The understanding of the complex interactions of cognition, stress and immunity will provide the basement to suggest suitable countermeasures for the prevention of the unwanted immunological effects of stressful conditions during space mission as well as on Earth.

Previous Flight Experiments

1.) IMMUNO (IMM) - Neuroendocrine and immune responses in humans during and after long term stay at ISS
2005 - 2013 - ISS Increment 12 to 36

2.) Flight control experiments on acute, stress associated effects during parabolic flight campaigns (PFC)

3.)
Parallel Earth bound control experiments during bedrest and in confined conditions (MARS500, CHO2ICE at the Antarctic bases Concordia and Neumayer III)
CoSi-500 Study - Confinement for 500 days - Evaluation of Stress and Immunity
2009 - Mars105
2010 - 2011 - Mars500


Figure 1: Hypotheses: All stress response systems contribute to the immune-modulating effects of stress. Stress seems to have dichotomy effects on immune function, either immune enhancing or immunosuppressive. In space, cosmonauts/astronauts are subject to multiple different stressors likely affecting all distinct stress response systems.

Figure 2: The study includes standard tests as well as newly evolved methodological and technical means to monitor (patho-) physiological, stress-responses and stress-dependent immune changes. A set of ex vivo experiments will help to estimate pre- and post-flight radiation assessment (e.g. a higher susceptibility of immune dysfunction). Non-invasive stress monitoring from pre-, in-and post-flight will be achieved (e.g. hair samples or expiratory breath samples). DTI brain imaging will be assessed pre- and post-flight. All parameters are subject to multidisciplinary analyses. All of the effectors regulating the immune response to stress that are described in this research can be achieved by Co-I ´s and the STMs together with the cosmonauts/astronauts and equipment on the ISS.

Figure 3: Protocol draft including a pre-(2x) and a post-flight assessment with up to four (4x) points. In-flight sampling is requested to be every ~ 30 to 45 days that is between 3 and maximally 5 times during a long duration mission of 12 months (indicated by arrows), total blood volumes are indicated.

Figure 4: Comparison between Immuno 1 and Immuno 2. Explanations: Blood samples and breath samples are collected once per time point. Saliva is collected in the morning and the evening (for the determination of circadian rhythmicity) and in the next morning upon completion of Day 2 Memory Tests. Hair is collected in the evening at the Saliva evening collection. The questionnaires are divided - in accordance to applicability - in a morning and evening set, in order to reduce the load of work in morning. CST (Current Stress Test), Backpain (BP), POMS (Profile of Mood State), GHQ: General Health Questionnaire-28, Memory Test includes computer presented pictures (emotional memory) and n-back-task (working memory) at Day 1, Day 2 = retrieval (computer based). ECG, pulse oximetry and actigraphy are placed in the night before blood processing draw (in accordance to hardware, TBC) and the continuously ECG/Actigraphy/Pulse oximetry monitoring period will be accordingly approx. 34-36 h later.

Test Subjects
Number of subjects desired:
9-10 subjects (males ~ 35-55 years of age)

Number of subjects required:
For statistical reasons 8 are considered as a minimum

Mission Duration
Minimum Mission Duration: 5 months

Ground Reference Experiments
The following study groups will serve as helpful cohort to estimate changes observed in Space:
- Previous ESA, IBMP and NASA research protocols on the ISS.
- Confinement at the Antarctic Concordia Base (French-Italian) and Neumayer III Station (German) & “historic” Arctic and Antarctic study groups (as been conducted by NASA STMs).
- Earth-bound confinement control groups e.g. confinement, either “historic” 110/240 or prospective studies (ESA, IBMP during MARS500, Bedrest “IMMUNO-BR”)
- Estimation of the biological parameters with the help of clinical studies e.g. from “historic” patients groups subjected to different forms of sub-acute and chronic stress. Further prospective studies in volunteers and patients are approved or are under current IRB review.

Long-duration spaceflight triggered a sustained stress dependent release of endocannabinoids combined with an aberrant immune activation mimicking features of people at risk for inflammation related diseases. These effects persisted in part 30 days after return to Earth. The currently available repertoire of in-flight testing as well as the post-flight observation periods need to be expanded to tackle the underlying mechanism for and consequences of these immune changes in order to develop corresponding mitigation strategies based on a personalized approach for future interplanetary space explorations.

Reference Document no 58 (see References section above or in the attachment section below) gives an comprehensive overview on the results of the research:
J.I. Buchheim, S. Matzel, M. Rykova, G. Vassilieva, S. Ponomarev, I. Nichiporuk, M. Hörl, D. Moser, K. Biere, M. Feuerecker, G. Schelling, D. Thieme, I. Kaufmann, M. Thiel, A. Choukèr, (2019), "Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight", Frontiers in Physiology, 10, DOI: 10.3389/fphys.2019.00085 ISSN=1664-042X, pp. 85.

EXPECTED RESULTS and HYPOTHESIS

General Hypothesis:
Long-duration space mission induces complex orchestrated and multidirectional stress responses of neural, endo-, paraand autocrine nature that will all affect the human immune system. In the context of the general hypothesis we focus on the following more detailed working hypotheses.

Working Hypotheses:
1.) Stressful living conditions in space due to confinement, workload and microgravity are significantly potentiated by experienced sleep alterations, back pain and moderate (sleep-) hypoxia, altogether affecting immunity as been triggered through the autonomic nervous system (ANS), immunotropic glucocorticoids (GC), the endocannabinoid (ECS), and the purinergic (PS) stress-response systems.

2.) Changes in ANS, GC, ECS and PC stress-response systems and alterations in immunity due to stress in space are associated with alterations in cognitive and emotional functions and may also be related to affective problems.
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J.I. Buchheim, S. Matzel, M. Rykova, G. Vassilieva, S. Ponomarev, I. Nichiporuk, M. Hörl, D. Moser, K. Biere, M. Feuerecker, G. Schelling, D. Thieme, I. Kaufmann, M. Thiel, A. Choukèr, (2019), "Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight", Frontiers in Physiology, 10, DOI: 10.3389/fphys.2019.00085 ISSN=1664-042X, pp. 85.
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Immuno 2: Examining the stress-related weakening of the immune system. Credit: DLR (CC-BY 3.0)

Figure 1: Hypotheses: All stress response systems contribute to the immune-modulating effects of stress. Stress seems to have dichotomy effects on immune function, either immune enhancing or immunosuppressive. In space, cosmonauts/astronauts are subject to multiple different stressors likely affecting all distinct stress response systems.

Figure 2: The study includes standard tests as well as newly evolved methodological and technical means to monitor (patho-) physiological, stress-responses and stress-dependent immune changes. A set of ex vivo experiments will help to estimate pre- and post-flight radiation assessment (e.g. a higher susceptibility of immune dysfunction). Non-invasive stress monitoring from pre-, in-and post-flight will be achieved (e.g. hair samples or expiratory breath samples). DTI brain imaging will be assessed pre- and post-flight. All parameters are subject to multidisciplinary analyses. All of the effectors regulating the immune response to stress that are described in this research can be achieved by Co-I ´s and the STMs together with the cosmonauts/astronauts and equipment on the ISS.
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Figure 3: Protocol draft including a pre-(2x) and a post-flight assessment with up to four (4x) points. In-flight sampling is requested to be every ~ 30 to 45 days that is between 3 and maximally 5 times during a long duration mission of 12 months (indicated by arrows), total blood volumes are indicated.

Figure 4: Comparison between Immuno 1 and Immuno 2. - also see section "Procedure".

Reference Document [58] J.I. Buchheim, S. Matzel, M. Rykova, G. Vassilieva, S. Ponomarev, I. Nichiporuk, M. Hörl, D. Moser, K. Biere, M. Feuerecker, G. Schelling, D. Thieme, I. Kaufmann, M. Thiel, A. Choukèr, (2019), "Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight", Frontiers in Physiology, 10, DOI: 10.3389/fphys.2019.00085 ISSN=1664-042X, pp. 85.
http://eea.spaceflight.es
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Fact sheet for Immuno 2 - in German and English language. Credit: DLR
 
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