Space flight has profound effects on the immune system of humans, monkeys and rodents. Several factors including microgravity, lack of load-bearing, stress, acceleration forces, and irradiation have been proposed to contribute to the changes of the immune system. However, the exact mechanisms by which these factors affect the immune system remain to be established. Simulation of these factors with ground animal models (e.g., hindlimb suspension in rodents) has been used to replicate the effects of space flight on immune system. Our recent studies have shown that opioids could induce Fas expression. In addition, restraint stress in mice induces Fas-mediated apoptosis in splenocytes in an endogenous opioid-dependent manner. Since space flight conditions resemble both physical and psychological stress to humans and animals, we hypothesize that immunosuppression during space flight is a result of the expression of Fas induced by increased production of endogenous opioids. We propose the following aims to test this hypothesis: 1) Determine the role of endogenous opioids in lymphocyte reduction induced by hindlimb suspension. At different times after suspension, mice will be treated with opioid receptor antagonists. Lymphocytes will be isolated from peripheral blood, spleen, and lymph nodes, and assayed for lymphocyte number, responsiveness to mitogenic stimulation, and the production of cytokines (INF-gamma, TNF, and IL-2) and antibodies. The number of apoptotic cells in the spleen and lymph nodes will be determined. 2) Since endogenous opioid production during space flight has not been studied, we will determine the level of endogenous opioids such as beta-endorphins, dynorphin, and enkephalin at different times after subjection to hindlimb suspension. 3) We will determine whether administration of anti-Fas ligand antibody or soluble recombinant Fas protein could block hindlimb suspension-induced lymphocyte reduction. In addition, the expression of Fas and FasL in animals subjected to hindlimb suspension will also be examined by northern blot analysis and surface staining. Furthermore, mice with Fas or FasL mutation will be used to verify the role of Fas in this process. The overall goal of these studies is to determine the mechanism(s) underlying immunosuppression associated with ground simulation of space flight, via endogenous opioids-modulated lymphocyte apoptosis. The results should lead to an understanding of the effects of space flight environment on human immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050222-03
Application #
6532882
Study Section
Special Emphasis Panel (ZRG1-SSS-4 (10))
Program Officer
Johnson, David R
Project Start
2001-08-01
Project End
2006-06-30
Budget Start
2002-08-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$332,381
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Genetics
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Ren, Guangwen; Su, Juanjuan; Zhang, Liying et al. (2009) Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27:1954-62
Ren, Guangwen; Su, Juanjuan; Zhao, Xin et al. (2008) Apoptotic cells induce immunosuppression through dendritic cells: critical roles of IFN-gamma and nitric oxide. J Immunol 181:3277-84
Ren, Guangwen; Zhang, Liying; Zhao, Xin et al. (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2:141-50
Ehirchiou, Driss; Xiong, Ying; Xu, Guangwu et al. (2007) CD11b facilitates the development of peripheral tolerance by suppressing Th17 differentiation. J Exp Med 204:1519-24
Xu, Guangwu; Zhang, Liying; Ren, Guangwen et al. (2007) Immunosuppressive properties of cloned bone marrow mesenchymal stem cells. Cell Res 17:240-8
Das, Gobardhan; Das, Jyoti; Eynott, Paul et al. (2006) Pivotal roles of CD8+ T cells restricted by MHC class I-like molecules in autoimmune diseases. J Exp Med 203:2603-11
Shi, Yufang; Liu, Catherine H; Roberts, Arthur I et al. (2006) Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res 16:126-33
Devadas, Satish; Das, Jyoti; Liu, Catherine et al. (2006) Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells. Immunity 25:237-47
Greeneltch, Kristy M; Kelly-Welch, Ann E; Shi, Yufang et al. (2005) Chronic morphine treatment promotes specific Th2 cytokine production by murine T cells in vitro via a Fas/Fas ligand-dependent mechanism. J Immunol 175:4999-5005
Yuan, Zeng-Rong; Wang, Ruoxiang; Solomon, Jennifer et al. (2005) Identification and characterization of survival-related gene, a novel cell survival gene controlling apoptosis and tumorigenesis. Cancer Res 65:10716-24

Showing the most recent 10 out of 17 publications