The overall goal of this project is to understand mechanisms of cellular immune reactions in the central nervous system (CNS). The hypothesis to be tested is that prominent surface expression of specific molecules on CNS resident cells, particularly endothelial cells, play critical roles in the pathogenesis of immune-mediated injury. We will use immunohistochemistry at the light and electron microscopic levels to localize specific proteins in the CNS, and in situ hybridization to determine sites of synthesis. (I). Class II major histocompatibility complex (Ia) molecules will be analyze in animal T cell immune response models. In experimental allergic encephalomyelitis (EAE) in inbred strains of mice and their F1 progeny we will determine if there is preferential expression of susceptible parent strain-specific Ia molecules in the in response to different myelin antigens and will develop an in vitro system for a lysis of Ia regulation on conventional and resident CNS antigen-presenting cells. Temporal sequences and cellular localization of resident cell Ia molecules will be analyzed in delayed hypersensitivity reactions to determine if cell surface Ia expression precedes or is a secondary effect of T cell infiltration in situ. (II). Endothelial cell surface molecules will be analyzed in human CNS inflammatory diseases. Effect of HIV-1 infection on endothelial cell expression of major histocompatibility complex molecules will be analyzed in patients with AIDS; HLA-DR-specific mRNA will be identified in multiple sclerosis (MS) and viral encephalitis; and fibronectin, a glycoprotein which enhances mononuclear cell attachment to endothelial cells, will be identified and its site of synthesis determined in MS. (III). Potential contributions to demyelination of antibodies to external surface myelin peptides will be determined by identifying protein sequences localized outer leaflets of CNS myelin which may be targets of immune-mediated injury and the comparing effects of monoclonal antibodies to synthetic peptides of various regions of myelin on clinical course and demyelination in EAE. These studies will provide further insights into regulation and cell surface interactions of molecules which participate in CNS immune responses and may contribute to the development of specific strategies for treatment of inflammatory and demyelinating CNS diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026773-06
Application #
3412792
Study Section
Neurology C Study Section (NEUC)
Project Start
1988-12-01
Project End
1994-03-31
Budget Start
1992-12-01
Budget End
1994-03-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Stanford University
Department
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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