This is a renewal application by Dr. William F. Hickey to study factors influencing the development of inflammation in the central nervous system (CNS) in the Lewis rat. The long-term goal is to identify the regulatory elements and cell surface molecules required for CNS inflammation to occur. The investigator has identified cell surface molecules defined by a panel of monoclonal antibodies (mAb), that appear to play a role in cell entry into the CNS and the ability of the CNS to support the development of inflammation. He proposes to utilize these reagents to delineate the specific changes that occur in the CNS which are associated with the development of inflammatory diseases.
Three specific aims are proposed. In the first aim, the investigator will define the changes which occur in a specific CNS site, the superior colliculus, which is usually resistant to EAE. He will target EAE inflammation to one superior colliculus following optic nerve transection, and compare the deafferented colliculus with the contralateral colliculus by immunohistochemistry, using the panel of mAbs which he has developed. He will also use RT-PCR to define relative changes in gene products, and will employ Differential Display PCR (DD-PCR) to further define genes that are differentially expressed in the deafferented vs. control colliculi. In the second aim, the investigator will define the early changes which occur in the CNS after encephalitogenic T cells arrive, but before onset of clinical disease, and distinguish the cascade of CNS changes following entry of encephalitogenic vs. nonencephalitogenic TH1 cells into the CNS. He will employ immunohistochemistry and RT-PCR to define these changes. As part of this aim, Dr. Hickey will also determine whether the passage of non-CNS-specific T cells into the CNS lowers the threshold of susceptibility to EAE. In the third aim, the investigator proposes to characterize the MAb-defined genes encoding membrane molecules that appear before or during the onset of EAE. Dr. Hickey postulates that some of the mAbs that he has produced define important cell surface molecules which play critical roles in the interactions of T cells with APCs and/or CNS endothelium. Ultimately, he hopes to obtain partial DNA sequences or clone the genes for these molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027321-11
Application #
2702988
Study Section
Special Emphasis Panel (ZRG1-NEUC (01))
Program Officer
Kerza-Kwiatecki, a P
Project Start
1988-09-01
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
2000-04-30
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Pathology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Williams, Kenneth C; Hickey, William F (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu Rev Neurosci 25:537-62
Sweitzer, Sarah M; Hickey, William F; Rutkowski, Maria D et al. (2002) Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: potential relationship to neuropathic pain. Pain 100:163-70
Kielian, Tammy; van Rooijen, Nico; Hickey, William F (2002) MCP-1 expression in CNS-1 astrocytoma cells: implications for macrophage infiltration into tumors in vivo. J Neurooncol 56:1-12
Kielian, T; Barry, B; Hickey, W F (2001) CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses. J Immunol 166:4634-43
Hickey, W F (2001) Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118-24
Ratcliffe, N R; Wegmann, K W; Zhao, R W et al. (2000) Identification and characterization of the antigen presenting cell in rat autoimmune myocarditis: evidence of bone marrow derivation and non-requirement for MHC class I compatibility with pathogenic T cells. J Autoimmun 15:369-79
Ratcliffe, N R; Hutchins, J; Barry, B et al. (2000) Chronic myocarditis induced by T cells reactive to a single cardiac myosin peptide: persistent inflammation, cardiac dilatation, myocardial scarring and continuous myocyte apoptosis. J Autoimmun 15:359-67
Yeager, M P; DeLeo, J A; Hoopes, P J et al. (2000) Trauma and inflammation modulate lymphocyte localization in vivo: quantitation of tissue entry and retention using indium-111-labeled lymphocytes. Crit Care Med 28:1477-82
Kielian, T; Hickey, W F (2000) Proinflammatory cytokine, chemokine, and cellular adhesion molecule expression during the acute phase of experimental brain abscess development. Am J Pathol 157:647-58
Williams, K C; Zhao, W; Politopoulou, G et al. (2000) Inhibition of experimental allergic encephalomyelitis with an antibody that recognizes a novel antigen expressed on lymphocytes, endothelial cells, and microglia. Lab Invest 80:313-26

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