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The overall laboratory hypothesis is that unbalanced monocyte
differentiation to inflammatory macrophage versus immunostimulatory
dendritic cells results in cytokine shock and immunosuppression in
traumatic patients. Post injury alterations in monocyte (MØ)
receptor expression and stimulation are examined at the molecular
(PCR, RPA, Microarray) cell expression (flow cytometry) and signal
transduction levels assessed as pivotal in altered MØ differentiation.
Early post injury mediators like prostaglandins and heat shock proteins
are being assessed as triggers for these receptor changes. The induction
of anergic and/or regulatory T lymphocytes by dysfunctional dendritic
cells is explored. Altered T cell activation, apoptosis and function
are also assessed in molecular and signal transduction experiments.
Regulatory and anergic T cells are being distinguished by unique receptor
expression and signaling. Finally, in combination with 11 other medical
centers including Stanford, Harvard, Washington U., Northwestern,
and the University of Washington, we are identifying chemokine and
other surface phenotypic markers for patients' developing immunoaberrances.
Microarray analysis is also being used to identify novel targets for
immunomodulation in these patients with systemic and chronic inflammatory
pathology.
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De AK, Laudanski K, Miller-Graziano CL.
Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating
Factor-Driven Macrophage Differentiation.
J Immunol 170:6355-6362, 2003.
Sheth K, Friel J, Nolan B, Miller-Graziano C, Bankey P.
Down-Regulated Circulating PMN Function after Injury Despite Enhanced p38 MAPK Activity.
Surg Infect 3:151-8, 2002.
Sheth K, De A, Nolan B, Friel J, Duffy A, Ricciardi R, Miller-Graziano C, Bankey P.
Heat shock protein 27 inhibits apoptosis in human neutrophils.
J Surg Res. 99:129-33, 2001.
Mitra P, De A, Ethier MF, Mimori K, Kodys K, Shibuta K, Mori M, Madison JM, Miller-Graziano C, Barnard GF.
Loss of chemokine SDF-1alpha-mediated CXCR4 signalling and receptor internalization in human hepatoma cell line HepG2.
Cell Signal. 13:311-9, 2001.
De AK, Kodys KM, Yeh BS, Miller-Graziano C.
Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus.
J Immunol. 165:3951-8, 2000.
De AK, Kodys KM, Pellegrini J, Yeh B, Furse RK, Bankey P, Miller-Graziano CL.
Induction of global anergy rather than inhibitory Th2 lymphokines mediates posttrauma T cell immunodepression.
Clin Immunol. 96:52-66, 2000.
Pellegrini JD, De AK, Kodys K, Puyana JC, Furse RK, Miller-Graziano C.
Relationships between T lymphocyte apoptosis and anergy following trauma.
J Surg Res. 88:200-6, 2000.
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