Multiple Organ Dysfunction Syndrome (MODS) in trauma patients is linked to a subset of trauma patients who develop global T cell anergy and are at highest risk of mortality and morbidity. Some trauma patients' T lymphocytes become unresponsive (anergic), then recover from anergy but others do not perhaps because their anergic T cells are actively maintaining their anergy, thereby increasing their risk of MODS. We hypothesize that the subset of trauma patients who develop MODS and experience long-term T cell global anergy activate a repertoire of inhibitory signaling pathways actively perpetuating their T cell anergy. We also postulate that altered receptor expression is both causal and/or typical of these long-term anergic and anergy inducing T cells. We further contend that multiple different pathways of T cell anergy can occur post- injury and that these anergy inducing triggers will act through defined but characteristically different inhibitory block in signal transduction pathways critical to T cell activation and cytokine production. Three recently described long-term anergy- inducing, T cell signaling pathways have been targeted for investigation based on our preliminary patient T cell data. Reduced CD28 co-stimulation during activation through T cell receptor complex (TCR); Failed T cell downregulation of CTLA4 expression resulting in CTLA4 triggering of negative signaling; Upregulation of T cell inhibitory receptors activating SHP-1 phosphatase with consequent dephosphorylation of critical TCR associated phosphotyrosine kinases (PTK).
Our Specific Aims are: 1) Determine if known T cell inhibitory signaling pathways are activated in trauma patients' anergic T cells and corresponds to prolonged anergy and increasing Marshall's MODS scores. 2) Delineate if reversal of post-trauma T cell anergy by exogenous cytokines and/or exogenous co-stimulation varies depending on the mechanisms of anergy induction. 3) Determine if patients' anergic T lymphocytes actively immunosuppress normal T lymphocyte activation or mediate Dendritic cell (DC) dysfunction disrupting both T cell immune function and monocyte/macrophage inflammatory/immunostimulatory balances thereby pivotally contributing to post trauma pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM065237-01S2
Application #
6595069
Study Section
Special Emphasis Panel (ZRG1 (37))
Program Officer
Somers, Scott D
Project Start
2001-08-01
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
1
Fiscal Year
2002
Total Cost
$9,431
Indirect Cost
Name
University of Rochester
Department
Surgery
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Bandyopadhyay, Gautam; Bandyopadhyay, Sanjukta; Bankey, Paul E et al. (2014) Elevated postinjury thrombospondin 1-CD47 triggering aids differentiation of patients' defective inflammatory CD1a+dendritic cells. J Leukoc Biol 96:797-807
Bandyopadhyay, Gautam; Bankey, Paul E; Miller-Graziano, Carol L (2012) Trauma patients' elevated tumor necrosis related apoptosis inducing ligand (TRAIL) contributes to increased T cell apoptosis. Clin Immunol 145:44-54
Bankey, Paul E; Banerjee, Sanjib; Zucchiatti, Andrea et al. (2010) Cytokine induced expression of programmed death ligands in human neutrophils. Immunol Lett 129:100-7
Bandyopadhyay, Gautam; De, Asit; Laudanski, Krzysztof et al. (2007) Negative signaling contributes to T-cell anergy in trauma patients. Crit Care Med 35:794-801
Hilchey, Shannon P; De, Asit; Rimsza, Lisa M et al. (2007) Follicular lymphoma intratumoral CD4+CD25+GITR+ regulatory T cells potently suppress CD3/CD28-costimulated autologous and allogeneic CD8+CD25- and CD4+CD25- T cells. J Immunol 178:4051-61
Laudanski, Krzysztof; De, Asit; Miller-Graziano, Carol (2007) Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells. Eur J Immunol 37:2812-24
Laudanski, Krzysztof; Miller-Graziano, Carol; Xiao, Wenzhong et al. (2006) Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways. Proc Natl Acad Sci U S A 103:15564-9
Laudanski, Krzysztof; De, Asit; Pellegrini, Joanmarie et al. (2006) Simultaneous aberrations in Mphi and T cell function adversely affect trauma patients' clinical outcome: a possible faulty IL-13 feedback loop. Clin Immunol 118:332-41