The long range goal of this project is to understand mechanisms of cellular immune reactions in the central nervous system (CNS). The overall hypothesis is that surface expression of specific molecules on inflammatory and CNS resident cells play critical roles in immune- mediated injury. CNS tissue samples from animals with experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis (MS), and from patients with CNS diseases are studied using routine histology and immunohistochemistry at the light microscopic and ultrastructural levels to visualize directly the locations of cell surface molecules that are effectors and targets in CNS immune reactions. The studies to be performed in the proposed grant period will determine: 1. (A) The regions of myelin proteolipid protein (PLP) that are localized on the external surface (intermediate dense line) and those epitopes that are localized on the cytoplasmic face (major dense line) in compact CNS myelin and (B) whether antibodies with specificities to epitopes on the external surface induce more demyelination than antibodies to epitopes on the cytoplasmic face in vivo in an acute EAE model. 2. Whether cell-surface integrin receptors of vitronectin and laminin are expressed on inflammatory cells in lesions of EAE and MS and whether this expression and colocalization with vitronectin and laminin correlate with the degree of inflammation and demyelination. 3. Whether the temporal dynamics, extent of infiltration of T cell receptor V tau delta+ cells and their target heat shock proteins correlate with clinical manifestations and type and degree of histologic injury in a mouse model of chronic EAE. This research addresses both the normal molecular structure of CNS myelin and mechanisms of demyelination in MS and other demyelinating diseases. Because integrins are both used by neoplastic cells for tissue invasion and by microorganisms as receptors, the results will also have implications for the pathogenesis of CNS metastatic tumors and infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS026773-07A1
Application #
2266088
Study Section
Neurology C Study Section (NEUC)
Project Start
1988-12-01
Project End
1998-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Sobel, R A (2000) Genetic and epigenetic influence on EAE phenotypes induced with different encephalitogenic peptides. J Neuroimmunol 108:45-52
Smith-Norowitz, T A; Sobel, R A; Mokhtarian, F (2000) B cells and antibodies in the pathogenesis of myelin injury in Semliki Forest Virus encephalomyelitis. Cell Immunol 200:27-35
Chang, T T; Jabs, C; Sobel, R A et al. (1999) Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis. J Exp Med 190:733-40
Beland, J L; Sobel, R A; Adler, H et al. (1999) B cell-deficient mice have increased susceptibility to HSV-1 encephalomyelitis and mortality. J Neuroimmunol 94:122-6
Mokhtarian, F; Zhang, Z; Shi, Y et al. (1999) Molecular mimicry between a viral peptide and a myelin oligodendrocyte glycoprotein peptide induces autoimmune demyelinating disease in mice. J Neuroimmunol 95:43-54
van der Maesen, K; Hinojoza, J R; Sobel, R A (1999) Endothelial cell class II major histocompatibility complex molecule expression in stereotactic brain biopsies of patients with acute inflammatory/demyelinating conditions. J Neuropathol Exp Neurol 58:346-58
Santambrogio, L; Lees, M B; Sobel, R A (1998) Altered peptide ligand modulation of experimental allergic encephalomyelitis: immune responses within the CNS. J Neuroimmunol 81:1-13
Sobel, R A; Hinojoza, J R; Maeda, A et al. (1998) Endothelial cell integrin laminin receptor expression in multiple sclerosis lesions. Am J Pathol 153:405-15
Williams, P L; Sobel, R A; Sorensen, K N et al. (1998) A model of coccidioidal meningoencephalitis and cerebrospinal vasculitis in the rabbit. J Infect Dis 178:1217-21
Sobel, R A (1998) The extracellular matrix in multiple sclerosis lesions. J Neuropathol Exp Neurol 57:205-17

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