Long-duration space flight and microgravity have been shown to have negative impacts on immune function. Impaired immune function, along with radiation exposure from galactic cosmic rays (GCR) and solar particle events (SPE), has the potential to increase risks for latent viral reactivation and various forms of cancer during exploration missions. Natural Killer (NK)-cells are a critical component of the immune system and play a vital role in detection and regulation of virus-infected cells. Additionally, T-cell receptor (TCR) T cells are a critical component in both anti-tumor and anti-viral surveillance.
Impairments in NK-cell and T cell function during space travel could adversely affect immune surveillance against cancer and viruses at a time when crewmembers are exposed to environmental factors that promote latent viral reactivation and possibly tumor formation. In addition to studying the effects of simulated microgravity on immune dysfunction, preliminary research shows that zoledronic acid (ZOL) in combination with Interleukin-2 (IL-2) to be a potential countermeasure to NK-cell and T cell impairment. IL-2 has been shown to augment NK-cell cytotoxicity by increasing activation, perforin-binding and proliferation. This increase in NK-cell function might override the suppression of function induced by microgravity. Similarly, ZOL has been shown to augment T cell function and proliferation.
Reduced immunity in NK-cell function has been observed in ISS crewmembers on their first mission on the station, and in vitro tests using a rotary cell culture system to replicate microgravity has demonstrated impaired ability of NK-cells to regulate tumor cells in as little as 12 hours in this microgravity analog. Because T cells have emerged as key players in both anti-tumor and anti-viral immune surveillance, this experiment will observe their behavior in vivo, along with NK-cell function, in simulated microgravity.
This study has the following specific aims:
- Determine the effect of simulated microgravity (SMG) on the anti-tumor capacity of human NK-cells and ?d-T cells in vivo.
- Determine the effect of systemic administration of IL-2 and ZOL on the function of NK and T cells.
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A humanized mouse model using the NOD-scid-IL2R?null (NSG) mouse has been developed to determine the effects of adoptively transferred human peripheral blood leukocytes on the anti-tumor activity of both liquid (e.g. leukemia) and solid (e.g. neuroblastoma) human tumor growth in vivo. NSG mice are genetically manipulated to have immature innate and adaptive immune systems making them suited for xeno transplant studies. This experiment will use five groups (Static, rotational control, simulated microgravity, PBMC only and tumor only) in each specific aim (2 aims), 8 mice per group with two kinds of tumors. NSG mice adoptively transferred with human peripheral blood mononuclear cells (PBMCs), NK-cells and T cells will be infused with zoledronic acid (ZOL) and IL-2 as a potential countermeasure to microgravity-induced immune system impairment.
A rotary cell culture system (RCCS) will be used to simulate microgravity in a ground analog. PBMCs are loaded into high-aspect ratio vessels. Vessel ‘A’ (SMG) rotates around a horizontal axis facilitating cells to be in a simulated microgravity environment by randomizing gravity vector in a low shear quiescent environment. Vessel ‘B’ (Rotational Control) rotates around a vertical axis simulating the rotational shear stress. Vessel ‘C’ (STATIC) remains stationary experiencing 1G gravitational force.
Immuncompromised NSG mice will be engrafted with two separate tumor models: K562 Chronic Myeloid Leukemia (CML) cell line for the liquid (blood) cancer, and SK-N-SH neuroblastoma cell line because it is a solid tumor. There two different models will allow this study to enumerate and determine the phenotypic characteristics of the tumor infiltrating cells following exposure to SMG. All tumors will be luciferase tagged so that growth can be accurately quantified in vivo and non-lethally by spectral imagery and bioluminescent intensity. The same models and outcome measures will be used to determine the efficacy of ZOL+IL-2 therapy as potential countermeasure, as outlined in the second specific aim of this study.
This experiment is currently in progress. Results will be made available at a later date.
Mylabathula PL, Li L, Bigley AB, Markofski MM, Crucian BE, Mehta SK, Pierson DL, Laughlin MS, Rezvani K, Simpson RJ. Simulated microgravity disarms human NK-cells and inhibits anti-tumor cytotoxicity in vitro. Acta Astronaut. 2020 Sep;174:32-40. [DOI]
Crew health and performance is critical to successful human exploration beyond low Earth orbit.
The Human Research Program (HRP) investigates and mitigates the highest risks to human health
and performance, providing essential countermeasures and technologies for human space exploration.
Risks include physiological and performance effects from hazards such as radiation, altered gravity,
and hostile environments, as well as unique challenges in medical support, human factors,
and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify
the approach and research activities planned to address these risks, which are assigned to specific
Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.
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