Lymphocytes are the predominant leukocyte found in central nervous system (CNS) inflammatory lesions in multiple sclerosis (MS) and other CNS inflammatory diseases. Lymphocytes may contribute both to the initiation and maintenance of CNS inflammation via antigen-specific interactions that occur during their baseline trafficking into normal CNS for the purpose of immune surveillance. Chemoattractant cytokines, or chemokines, are small secreted proteins that recruit lymphocytes into parenchymal tissues during both homeostatic and inflammatory states. Although the mechanisms that recruit lymphocytes specifically into the CNS during this baseline trafficking are unknown, our preliminary data that chemokines are constitutively expressed by the CNS and that activated lymphocytes traffic into normal CNS tissues suggests that chemokines may play an important role in this process. With the Independent Scientist Award (K02), the applicant will place an intensive research focus toward determining the chemokines and chemokine receptors that direct the trafficking of T lymphocytes into normal CNS tissues in vivo. Using an in vivo trafficking model, we will examine the role of chemokine receptors in the movement of T cells into normal CNS and assess the loss of chemokine receptor activity in this process using mice with targeted deletions of appropriate chemokine receptors. We will then go on to determine whether inhibition of the baseline trafficking of lymphocytes into the CNS affects the development of the murine CNS inflammatory disease, experimental autoimmune encephalomyelitis (EAE), which is a model for MS. The applicant is a principal investigator at the MGH Center for Immunology and Inflammatory Diseases, which provides a rich intellectual and experimental environment to establish the groundwork for these investigations. As evidenced by almost nine years of research in the neurosciences, the applicant remains firmly committed to a long-term career in basic science investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02NS045607-04
Application #
6908914
Study Section
NST-2 Subcommittee (NST)
Program Officer
Utz, Ursula
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$176,418
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
McCandless, Erin E; Piccio, Laura; Woerner, B Mark et al. (2008) Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am J Pathol 172:799-808
Klein, Robyn S; Diamond, Michael S (2008) Immunological headgear: antiviral immune responses protect against neuroinvasive West Nile virus. Trends Mol Med 14:286-94
Zhang, Bo; Chan, Ying Kai; Lu, Bao et al. (2008) CXCR3 mediates region-specific antiviral T cell trafficking within the central nervous system during West Nile virus encephalitis. J Immunol 180:2641-9
Klein, Robyn S (2008) A moving target: the multiple roles of CCR5 in infectious diseases. J Infect Dis 197:183-6
McCandless, Erin E; Zhang, Bo; Diamond, Michael S et al. (2008) CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis. Proc Natl Acad Sci U S A 105:11270-5
McCandless, Erin E; Klein, Robyn S (2007) Molecular targets for disrupting leukocyte trafficking during multiple sclerosis. Expert Rev Mol Med 9:1-19
Sitati, Elizabeth; McCandless, Erin E; Klein, Robyn S et al. (2007) CD40-CD40 ligand interactions promote trafficking of CD8+ T cells into the brain and protection against West Nile virus encephalitis. J Virol 81:9801-11
Archambault, Angela S; Sim, Julia; McCandless, Erin E et al. (2006) Region-specific regulation of inflammation and pathogenesis in experimental autoimmune encephalomyelitis. J Neuroimmunol 181:122-32
Gimenez, Mary Ann; Sim, Julia; Archambault, Angela S et al. (2006) A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. Am J Pathol 168:1200-9
Kim, Joong Hee; Budde, Matthew D; Liang, Hsiao-Fang et al. (2006) Detecting axon damage in spinal cord from a mouse model of multiple sclerosis. Neurobiol Dis 21:626-32

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