Abstract

Macrophages play critical roles both as pro-inflammatory cells and as destructive effector cells in non-septic inflammatory diseases such as arthritis, vasculitis, and multiple sclerosis. The objective of this project is to determine the complex sequence of interactions between T cells and macrophages involved in the pathogenesis of autoimmune inflammatory diseases and to identify specific molecules involved that might be useful as therapeutic targets. CD4O:CD4O-ligand interactions have been shown to play a major role in T cell signaling of macrophage activation. Although the macrophage signaling ability of T cells is reduced in CD4OL-knockout mice, it is not absent. This study will examine established T cell clones generated from CD4OL-knockout mice to identify CD4O-independent signaling of macrophage accessory, inflammatory, and effector function. Transgenic T cells expressing the receptor for myelin basic protein will be used to study the initial interactions between naive T cells and macrophages in the presence or absence of functional CD40:CD4O-ligand interactions. The role of cytokines co-stimulatory for T cells or costimulatory for macrophages in augmenting T cell signaling of macrophage function will also be evaluated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI034875-04A1
Application #
2404067
Study Section
Immunobiology Study Section (IMB)
Project Start
1994-01-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
East Tennessee State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Johnson City
State
TN
Country
United States
Zip Code
37614

  Publications

Mukhopadhyay, A; Suttles, J; Stout, R D et al. (2001) Genetic deletion of the tumor necrosis factor receptor p60 or p80 abrogates ligand-mediated activation of nuclear factor-kappa B and of mitogen-activated protein kinases in macrophages. J Biol Chem 276:31906-12
Hoellman, J R; Suttles, J; Stout, R D (2001) Panning T cells on vascular endothelial cell monolayers: a rapid method for enriching naive T cells. Immunobiology 203:769-77
Clemons-Miller, A R; Cox, G W; Suttles, J et al. (2000) LPS stimulation of TNF-receptor deficient macrophages: a differential role for TNF-alpha autocrine signaling in the induction of cytokine and nitric oxide production. Immunobiology 202:477-92
Suttles, J; Milhorn, D M; Miller, R W et al. (1999) CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway. A target of interleukin (il)-4 and il-10 anti-inflammatory action. J Biol Chem 274:5835-42
Stout, R D; Suttles, J (1997) T cell signaling of macrophage function in inflammatory disease. Front Biosci 2:d197-206
Poe, J C; Wagner Jr, D H; Miller, R W et al. (1997) IL-4 and IL-10 modulation of CD40-mediated signaling of monocyte IL-1beta synthesis and rescue from apoptosis. J Immunol 159:846-52
Krishnaswamy, G; Lakshman, T; Miller, A R et al. (1997) Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids. J Interferon Cytokine Res 17:167-76
Suttles, J; Evans, M; Miller, R W et al. (1996) T cell rescue of monocytes from apoptosis: role of the CD40-CD40L interaction and requirement for CD40-mediated induction of protein tyrosine kinase activity. J Leukoc Biol 60:651-7
Miller, A R; Suttles, J; Stout, R D (1996) Cytokine priming reduces dependence on TNF-R2 for TNF-alpha-mediated induction of macrophage nitric oxide generation. J Interferon Cytokine Res 16:1055-63
Stout, R D; Suttles, J; Xu, J et al. (1996) Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. J Immunol 156:8-11

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