Impaired host responses after trauma or surgery (traumatic stress) render patients susceptible to sepsis thus greatly increasing morbidity, mortality and cost. T cell dysfunction is central to impaired host defenses after traumatic stress and is characterized by decreased proliferation, and production of cytokines (Interleukin 2 and interferon gamma) and a decrease in the number of T cell receptors (TCR) expressed on the cell membrane as a result of decreased L, chain. Myeloid cells are known to cause T cell dysfunction in traumatic stress, but the nature of these cells and how they cause T cell dysfunction is unclear. Our laboratory has recently found that traumatic stress induces the activation of a distinct immature myeloid cell population expressing both CD1 lb+ and GR1+ markers. These cells infiltrate the marginal zones of the spleen within 6 hours after trauma and by 12 hours constitute up to 15% of all spleen cells. Trauma-induced immature myeloid GDI lb+/GR-l+ cells (TIIMC) decrease T cell proliferation, impair cytokine production and decrease TCR zeta, chain expression. TIIMC also express very high levels of arginase 1 (ARG1) and possibly the cationic aminoacid transporter Cat2b and therefore appear to deplete arginine, an amino acid necessary for T cell function. Based on these observations we hypothesize that traumatic stress generates specific signals which induce arginase 1 expression in a distinct immature myeloid cell population that can alter T-cell function through arginine depletion. Our goals are to determine the mechanisms by which ARG1 in TIIMC causes T cell dysfunction, to identify the signals that induce and sustain the production of ARG1 in TIMC and to develop strategies designed to block or overcome T cell dysfunction after traumatic stress. We will answer these questions using a highly reproducible model of traumatic stress, in which ARG1 production is proportional to the severity of injury. We believe that the identification of an immature myeloid cell in a murine model of trauma is a novel observation that will allow us to understand T cell dysfunction in trauma and evaluate therapeutic strategies with translational potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065914-03
Application #
7214708
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$234,715
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Bryk, Jodie; Ochoa, Juan B; Correia, M Isabel Td et al. (2008) Effect of citrulline and glutamine on nitric oxide production in RAW 264.7 cells in an arginine-depleted environment. JPEN J Parenter Enteral Nutr 32:377-83
Caba, David; Ochoa, Juan B (2007) How many calories are necessary during critical illness? Gastrointest Endosc Clin N Am 17:703-10
Popovic, Petar J; Zeh 3rd, Herbert J; Ochoa, Juan B (2007) Arginine and immunity. J Nutr 137:1681S-1686S

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