Validation of Procedures for Monitoring Crewmember Immune Function (Integrated Immune) - 01.10.19

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ISS Science for Everyone

Science Objectives for Everyone
Validation of Procedures for Monitoring Crew Member Immune Function (Integrated Immune) will assess the clinical risks resulting from the adverse effects of space flight on the human immune system and will validate a flight-compatible immune monitoring strategy. To monitor changes in the immune system, researchers collect and analyze blood, urine and saliva samples from crewmembers before, during and after space flight.
Science Results for Everyone
Before we can safefy travel to distant places like an asteroid or Mars, scientists need to better understand how space flight affects their immune systems. The Integrated Immune investigation use an in-flight monitoring strategy, tested in the Haughton-Mars Project in the Arctic, to measure white blood cell count and stress hormones in Shuttle and ISS crew members. It is found that short missions caused greater initial stress than longer ones, perhaps because of training differences for short verus long-term missions. Researchers conclude that ISS pre-flight training does a good job of reducing stress.  These monitoring techniques could be applied to infection epidemics and in remote locations as well as during space missions.
Spaceflight anemia may be less of a concern for exploration crewmembers than previously believed. This recent longitudinal study found that for long-duration spaceflights, crewmembers actually showed an increased concentration of red blood cells, mean corpuscular volume, hemoglobin, and platelet concentration. These findings led researchers to conclude that earlier reports of reduced hematologic parameters may be an early adaptation to microgravity that may be somewhat compensated for after spending more time aboard the International Space Station (ISS) (Kunz, 2017).

The following content was provided by Clarence F. Sams, Ph.D., and is maintained in a database by the ISS Program Science Office.
Experiment Details

OpNom: Integrated Immune

Principal Investigator(s)
Clarence F. Sams, Ph.D., Johnson Space Center, Houston, TX, United States

Raymond P. Stowe, Ph.D., Microgen Laboratories, La Marque, TX, United States
Peter Uchakin, Ph.D., Mercer University School of Medicine, Macon, GA, United States
Brian E. Crucian, Ph.D., NASA Johnson Space Center, Houston, TX, United States
Duane L. Pierson, Ph.D., NASA Johnson Space Center, Houston, TX, United States
Satish K. Mehta, Ph.D., Enterprise Advisory Services Incorporated, Houston, TX, United States
Boris V. Morukov, Ph.D., M.D., Institute of Medical and Biological Problems, Moscow, Russia

NASA Johnson Space Center, Human Research Program, Houston, TX, United States

Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)

Sponsoring Organization
Human Exploration and Operations Mission Directorate (HEOMD)

Research Benefits
Earth Benefits, Scientific Discovery, Space Exploration

ISS Expedition Duration
October 2007 - September 2012

Expeditions Assigned

Previous Missions
Increment 16 was the first mission for Integrated Immune.

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Experiment Description

Research Overview

  • There is ample postflight evidence to suggest that space flight has a negative effect on the immune system; however, little in-flight data has been collected. The in-flight data that exists suggests that immune dysregulation occurs during flight. There are several possible causes ranging from microgravity, stress and radiation, just to name a few. Complications arising from an immune system dysregulation have the potential to pose a clinical risk for exploration class space missions.

  • In order to develop countermeasures to reduce in-flight immune dysfunction, a monitoring strategy must be developed.

  • The objective of this study is to validate a monitoring strategy that will allow future countermeasures to be developed.

The Validation of Procedures for Monitoring Crewmember Immune Function (Integrated Immune) is designed to develop and validate an immune monitoring strategy consistent with operational flight requirements and constraints. There are no procedures currently in place to monitor immune function or its influence on crew health. Immune dysregulation has been demonstrated to occur during space flight, yet little in-flight immune data has been generated to assess this clinical problem. Integrated Immune assesses the clinical risks resulting from the adverse effects of space flight on the human immune system and will validate a flight-compatible immune monitoring strategy. Characterization of the clinical risk and the development of a monitoring strategy are necessary prerequisite activities prior to validating countermeasures.

Preflight, in-flight and postflight assessments are performed as part of the Integrated Immune investigation. The in-flight samples allow investigators to assess the distinction between legitimate in-flight alterations, and the physiological stresses of landing, which are believed to alter landing day assessments. The overall status of the immune system during flight (activation, deficiency, dysregulation) and the response of the immune system to specific latent virus reactivation, (known to occur during space flight) are thoroughly assessed.

Following completion of the investigation, the data will be evaluated to determine the optimal set of assays for routine monitoring of crewmember immune system function. It is intended that the determined set of relevant assays will be incorporated into the Clinical Status Evaluation (CSE) and utilized to monitor the effectiveness of human medical countermeasures related to immune function (exercise, medication, diet regulation-supplementation, immune modulators, etc.). In addition, the assays validated here have significant benefits for the routine monitoring of crewmember's immune system status with regard to diagnosis and prognosis of immune-related disease states.

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Space Applications
The study will result in the validation of a monitoring strategy that allows the development of effective countermeasures, which when implemented, will safeguard the health of the crew during long-duration space missions.

Earth Applications
The data collected during this investigation may lead to a greater understanding of how the immune system is affected by different factors from stress to the environment. This data could potentially be used to help develop new treatments and preventative measures for immune dysfunctions.

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Operational Requirements and Protocols

Preflight, each subject performs two sessions: one at L-180 (launch minus 180) days and another at L-45 days. Each session consists of a health survey, four liquid saliva collections (performed every other day), blood draw, 24-hour urine and dry book saliva sample collection occurring on the day between the second and third liquid saliva collection.

Postflight, each long duration subject performs two sessions: one at R+0 collecting four liquid saliva samples collected every other day starting on R+0 in conjunction with a blood draw and 24-hour urine collection. The second session occurs at R+30 days collecting four liquid saliva samples (performed every other day) with a blood draw and 24-hour urine collection occurring on the day between the second and third liquid saliva collections. Dry book saliva samples are collected on R+1 and R+30 days. A health survey is completed in conjunction with both post-flight sessions. Each short duration subject performs two post-flight sessions: one at R+0 collecting blood, 24-hour urine and dry saliva. The second is performed at R+14 collecting the same set of measurements as obtained on R+0. Liquid saliva is collected every other day for this entire duration (R+0 to R+14).

In flight, only blood and saliva samples are collected. There is no urine sample requirement for in-flight operations. Subjects perform three sessions in-flight: early, mid and late increment. For the one-year mission, four sessions will be performed - one in conjunction with every Soyuz vehicle return.  Each session consists of four liquid saliva collections (performed every other day), with a blood draw and dry book saliva sample collection occurring on the last day of the liquid saliva collections. A health survey is also completed during a subject’s early and mid-mission sessions. For the late increment session, the final liquid saliva sample, the blood draw and dry book saliva sample collections occur on R-1. Blood samples are required to be returned for ground analysis within 48 hours of collection; therefore, the blood draws must occur in conjunction with a Shuttle or Soyuz flight to ISS.

Operations for this experiment consist of three types of sample collections: blood, urine and saliva. There are two types of saliva samples collected. Liquid saliva samples require the subject to soak a piece of cotton (or inert polymer) with saliva and place the material in a salivette bag. Dry book saliva samples are collected on filter paper bound in a small, specialized book at certain time intervals throughout the collection day. For preflight and postflight baseline data collection only, 24-hour urine collections require the subject to collect all urine starting with the first void of the day and continuing for a full 24-hour period.
Very little hard data exists regarding in-flight adverse medical events and the body’s ability to recover from such events during space flight. Of particular concern are conditions related to immunology; such as allergies, rashes, hypersensitivities, infections and wound healing. The data that does exist is often sequestered due to medical confidentiality. Therefore, in addition to collecting blood, saliva and urine, crewmembers will be requested to complete an immunology health survey.

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Decadal Survey Recommendations

Animal and Human Biology AH13
Animal and Human Biology AH14

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Results/More Information

In July 2002 NASA conducted a comprehensive immune assessment on the Haughton-Mars Project field team members. This project validated sampling methods, and laboratory results indicated that changes in immune function and stress hormone in the HMP field participants were similar to those observed in astronauts following space flight. Taken together, these data support the establishment of the HMP as a unique ground-based space flight and planetary exploration test bed that may have significant utility for terrestrial human physiology studies (Crucian et al. 2007).

Building on knowledge gained from ground-base field research, i.e. the HMP, Stowe et al. 2011 performed a study to determine if space flight duration has an effect on the levels of stress hormones. Researchers collected multiple preflight and postflight samples from Shuttle and ISS crewmembers from 2007 onward and found that Shuttle crewmembers on short missions, lasting about 2 weeks, experienced greater initial stress, even prior to launch, than crewmembers leaving for a much longer 6-month tour on board the ISS. After short-duration missions, white blood cell (WBC) counts were elevated and typical stress-induced shifts were observed, and a general immunity assessment confirmed a parallel decrease in immune function. Changes in monocytes, a type of WBC, parameters and defense signaling capacity may also impact overall crewmember immune system health (Crucian et al. 2007). ISS crewmembers, by contrast, did not show increased cortisol stress hormone levels at any time prior to launch, and a plausible explanation is the training, which differs greatly for these astronauts who are prepared mentally for long-duration flights that are psychologically challenging, is much longer and diverse than Shuttle astronauts. Stress hormones returned to preflight levels for both groups after a few days back on Earth. In addition, approximately 50% of the subjects had very high WBC counts which have typically been associated with increased stress hormones at landing, but it is important to note that such elevated values are indicative of infection or disease in otherwise healthy individuals and may mask true infection. Unexpectedly, some subsets of white blood cells did not show normal response to the rise in stress hormones for long-duration crewmembers. Further study is needed to determine if this is a failure of these WBCs to properly respond to acute stress or if the blood production process is altered during long-duration spaceflight. These results agree with prior studies demonstrating the importance of mission duration in the magnitude of these changes. The authors conclude that the current ISS training successfully reduces stress, and interventions employed during this period in which astronauts are most accessible would likely produce the desired effects (Stowe et al. 2011).

Spaceflight anemia has been suggested by previous findings of reduced Red Blood Cells (RBC) during short-duration spaceflights. However, findings from short-duration flights may be confounded by early-adaptation to microgravity, and not represent human physiology during long-duration spaceflight. These data were derived from two longitudinal studies of astronauts, and examined the effects of long-duration spaceflight on the immune and hematological system. Blood samples were collected from 31 crewmembers before, during (3 time points: early, mid, late), and after their stay on the International Space Station (ISS). The hematologic parameters examined in the blood samples included RBC count, mean corpuscular volume (MCV), hemoglobin, and platelet concentration. In a repeated-measures statistical design, crewmembers served as their own controls. Results showed significant increases in MCV observed in-flight (3.9% at early test, 4.6% at mid-test, and 4.2% at late test) relative to baseline (L-180 days). Significant elevations in the concentrations of RBCs, platelets, and hemoglobin were also observed. These results suggest that spaceflight anemia may less of a concern during long-duration spaceflight than previously believed, and may be an early adaptation to microgravity. It should be noted that dehydration may artificially elevate blood cell concentrations. A subsequent study, simultaneously assessing blood plasma volume, will be necessary to confirm a lack of anemia in astronauts (Kunz, 2017).

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Results Publications

    Crucian BE, Babiak-Vazquez A, Johnston SL, Pierson DL, Ott CM, Sams CF.  Incidence of clinical symptoms during long-duration orbital spaceflight. International Journal of General Medicine. 2016 November 3; 9: 383-391. DOI: 10.2147/IJGM.S114188. PMID: 27843335.

    Spielmann G, Agha N, Kunz HE, Simpson RJ, Crucian BE, Mehta SK, Laughlin MS, Campbell J.  B-cell homeostasis is maintained during long duration spaceflight. Journal of Applied Physiology. 2018 November 29; epub. DOI: 10.1152/japplphysiol.00789.2018. PMID: 30496712.

    Crucian BE, Stowe RP, Mehta SK, Quiriarte HD, Pierson DL, Sams CF.  Alterations in adaptive immunity persist during long-duration spaceflight. npj Microgravity. 2015 September 3; 1: 15013. DOI: 10.1038/npjmgrav.2015.13.

    Crucian BE, Lee P, Stowe RP, Jones JA, Effenhauser R, Widen R, Sams CF.  Immune system changes during simulated planetary exploration on Devon Island, high arctic. BMC Immunology. 2007 May 23; 8(1): 7. DOI: 10.1186/1471-2172-8-7.

    Crucian BE, Zwart SR, Mehta SK, Uchakin P, Quiriarte HD, Pierson DL, Sams CF, Smith SM.  Plasma cytokine concentrations indicate that in vivo hormonal regulation of immunity is altered during long-duration spaceflight. Journal of Interferon and Cytokine Research. 2014 October 2; 34(10): 778-786. DOI: 10.1089/jir.2013.0129. PMID: 24702175.

    Kaur I, Simons ER, Castro VA, Ott CM, Pierson DL.  Changes in monocyte functions of astronauts. Brain, Behavior, and Immunity. 2005 November; 19(6): 547-554. DOI: 10.1016/j.bbi.2004.12.006. PMID: 15908177.

    Kaur I, Simons ER, Kapadia AS, Ott CM, Pierson DL.  Effect of Spaceflight on Ability of Monocytes To Respond to Endotoxins of Gram-Negative Bacteria. Clinical and Vaccine Immunology. 2008 Oct; 15(10): 1523-1528. DOI: 10.1128/CVI.00065-08.

    Crucian BE, Johnston SL, Mehta SK, Stowe RP, Uchakin P, Quiriarte HD, Pierson DL, Laudenslager ML, Sams CF.  A case of persistent skin rash and rhinitis with immune system dysregulation onboard the International Space Station. The Journal of Allergy and Clinical Immunology: In Practice. 2016 March 8; epub. DOI: 10.1016/j.jaip.2015.12.021. PMID: 27036643.

    Kunz HE, Quiriarte HD, Simpson RJ, Ploutz-Snyder RJ, McMonigal KA, Sams CF, Crucian BE.  Alterations in hematologic indices during long-duration spaceflight. BMC Hematology. 2017 September 8; 17: 12. DOI: 10.1186/s12878-017-0083-y.

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Ground Based Results Publications

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ISS Patents

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Related Publications

    Barrila J, Ott CM, LeBlanc CL, Mehta SK, Crabbe A, Stafford P, Pierson DL, Nickerson CA.  Spaceflight modulates gene expression in the whole blood of astronauts. npj Microgravity. 2016 December 8; 2: 16039. DOI: 10.1038/npjmgrav.2016.39.

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Related Websites

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image The image above is the kit containing all the items the crew will need for taking blood samples. Image courtesy of NASA, Johnson Space Center.
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image Pictures of the kit used to collect the saliva samples. The rolled gauze is displayed in the upper left-hand corner of the picture, which is placed into the mouth to absorb saliva. Image courtesy of NASA, Johnson Space Center.
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image NASA Image: ISS030E257695 - View of Dan Burbank,Expedition 30 Commander; and European Space Agency (ESA) Andre Kuipers,Expedition 30 Flight Engineer (FE),during Integrated Immune Blood Sample Draw at the Human Research Facility (HRF),in the Columbus Module.
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