NASA Human Research Program Investigators' Workshop (2012)
4194.pdf
IDENTIFICATION OF A MECHANISM FOR IMMUNE DYSFUNCTION INDUCED
BY SOLAR PARTICLE EVENT RADIATION AND HINDLIMB SUSPENSION
Y. Zhou1, H. Ni1, M. Li1, J. K. Sanzari2, A. R. Kennedy2, and D. Weissman1
1
Division of Infectious Diseases, Department of Medicine and 2 Department of Radiation
Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104
(dreww@mail.med.upenn.edu).
INTRODUCTION
Future space travel will include extended stays outside of the Earth’s magnetic field, which
offers protection from solar radiation. In addition to factors associated with space exploration
that can impair immune function, including altered nutritional intake, situational and
confinement stress, disturbance of circadian rhythms, and reduced weight-bearing, the effect of
radiation from solar particle events (SPEs) must also be considered. Astronauts could receive up
to 2 Gy of radiation to the bone marrow and up to 32 Gy to the skin during a strong SPE.
Numerous studies of the effect of conditions encountered during space travel or in land-based
models in animals and humans have descriptively identified numerous immune alterations. Using
models of spaceflight that encompass most of the described stresses likely to be encountered and
adding radiation that models the energy spectrum found during an SPE, we mechanistically
studied alterations in immune function.
RESULTS
We observed that both SPE-like radiation and hindlimb suspension led to systemic immune
activation and together, the immune activation was more severe and present for an extended
duration. The systemic immune activation was characterized by an acute elevation in the levels
of circulating type I interferons. Two acute phase proteins involved in the systemic response to
lipopolysaccharide (LPS), sCD14 and LPS binding protein, were also elevated for 4 days
following radiation during suspension. The etiology of the immune activation was identified as a
breakdown in the ability of the GI tract to contain commensal bacterial products, known as
microbial translocation. This was shown to be causal by finding elevated levels of circulating
LPS and the accumulation of LPS in the subepithelial tissue of the GI tract.
DISCUSSION
We report a mechanism of immune dysfunction, microbial translocation, caused by SPE-like
radiation and a land-based model of reduced weightbearing. Samples from astronauts on shuttle missions lasting 10 to 13 days and obtained 3-­‐4 hours and 15 days after landing, similarly found elevated levels of LPS binding protein, suggesting microbial translocation during spaceflight. Multiple studies of animals and humans during and in models of spaceflight
observed various types of immune dysfunction. This includes increases in anti-inflammatory
cytokines and decreases in TNF-α in LPS stimulated spleen cells, reductions in interferon-γ and
IL-2 secretion following stimulation of peripheral blood cells, decreased production of type I
interferons following stimulation, and reduced responsiveness to T cell mitogens. These
alterations to immune function are similarly observed in settings of increased immune activation
caused by microbial translocation. Future studies will determine the role and contribution of this
mechanism on the various immune deficiencies identified in models or actual spaceflight.
A major interest of the NSBRI is the identification of countermeasures for impairments to
physiologic functions. This is especially important for extended missions in which the only
treatments available are those brought with the mission. The development of countermeasures is
improved by the identification of the mechanisms behind the dysfunction.