Disruption of the Blood Brain Barrier (BBB) is common pathologic feature of numerous serious neurological diseases. Despite the enormous burden of morbidity and mortality due to these neurological diseases associated with CNS vascular permeability, the underlying molecular mechanisms of how inflammatory cells promote BBB disruption remain poorly understood. We have developed a novel murine model of CNS vascular permeability that provides a tractable approach to defining specific inflammatory mediators that disrupt the BBB in vivo using Theiler's virus infection. This murine model of BBB disruption is initiated by peptide-specific stimulation of CNS infiltrating CD8 T cells and is not mediated by TNF-a, IFN-?, LT?R and IL- 1. However, perforin is critical for both CNS vascular permeability and preservation of BBB tight junctions. Notably, MHC-identical C57BL/6 and 129 Svlm mice differ dramatically in susceptibility to PIFS, despite having identical CD8+ T cell responses and CTL activity. The goal of this proposal is to test our underlying hypothesis that CD8 T cells utilize perforin to initiate the disruption of cerebral endothelial cell BBB tight junctions. Specific modifier genes on the C57BL/6 and 129 SvIm mouse background are also critical for this process to occur. We will determine using this model: 1.) the cellular source of perforin necessary for BBB disruption, 2.) the role of hematopoetic cells in promoting disruption of the BBB, and 3.) the chromosome location of genetic factors that govern BBB disruption. We will use conventional genetic analysis, protein biochemistry, imaging, cellular immunology assays, molecular biology and retrovirus expression to determine the inflammatory factors that mediate disruption of the BBB. Identification of powerful factors that contribute to fatal CNS vascular permeability would define targets for therapeutic modification of the BBB. Such diseases characterized by disruption of the BBB including stroke, viral hemorrhagic fevers, cerebral malaria, HIV dementia, multiple sclerosis (MS), and shock. Increased understanding of BBB permeability could also benefit chemotherapy.

Public Health Relevance

Inflammation mediated blood brain barrier (BBB) disruption is a poorly understood, yet relatively common feature of numerous neurologic diseases. We have developed a novel murine model of CNS vascular permeability that can be utilized to define specific cellular interactions and inflammatory mediators that result in disruption of the BBB in vivo. Defining such factors is the first step towards novel therapeutic modification of BBB permeability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060881-06
Application #
8509031
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$324,518
Indirect Cost
$109,646
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bell, Michael P; Renner, Danielle N; Johnson, Aaron J et al. (2014) A CD8 T-cell epitope variant enhances immune targeting to a recombinant picornavirus vaccine antigen. Viral Immunol 27:361-6
Johnson, Holly L; Willenbring, Robin C; Jin, Fang et al. (2014) Perforin competent CD8 T cells are sufficient to cause immune-mediated blood-brain barrier disruption. PLoS One 9:e111401
Johnson, Holly L; Jin, Fang; Pirko, Istvan et al. (2014) Theiler's murine encephalomyelitis virus as an experimental model system to study the mechanism of blood-brain barrier disruption. J Neurovirol 20:107-12
Tutuncu, Melih; Tang, Junger; Zeid, Nuhad Abou et al. (2013) Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler 19:188-98
Johnson, Holly L; Hanson, Lisa M; Chen, Yi et al. (2013) Quantitative trait loci analysis reveals candidate genes implicated in regulating functional deficit and CNS vascular permeability in CD8 T cell-initiated blood-brain barrier disruption. BMC Genomics 14:678
Zivadinov, Robert; Pirko, Istvan (2012) Advances in understanding gray matter pathology in multiple sclerosis: are we ready to redefine disease pathogenesis? BMC Neurol 12:9
Johnson, Holly L; Chen, Yi; Suidan, Georgette L et al. (2012) A hematopoietic contribution to microhemorrhage formation during antiviral CD8 T cell-initiated blood-brain barrier disruption. J Neuroinflammation 9:60
Zivadinov, Robert; Weinstock-Guttman, Bianca; Pirko, Istvan (2011) Iron deposition and inflammation in multiple sclerosis. Which one comes first? BMC Neurosci 12:60
Pirko, I; Johnson, A J; Chen, Yi et al. (2011) Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis. Neuroimage 54:802-6
Denic, Aleksandar; Johnson, Aaron J; Bieber, Allan J et al. (2011) The relevance of animal models in multiple sclerosis research. Pathophysiology 18:21-9

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