Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) that is widely used as an animal model of multiple sclerosis (MS). In this proposal, we will test a novel model of the immunopathogenesis of EAE focusing on factors that drive chronic inflammation in the CNS. In preliminary studies we demonstrated that CD11c ( dendritic-like cells accumulate in white matter infiltrates during EAE. Furthermore, the lymphoid chemokines, CCL19, CCL21 and CXCL13, are upregulated in spinal cords of mice at EAE onset and steadily rise during disease progression. Based on these findings, we propose the following hypotheses: (i) CNS CD11c ( cells differentiate from resident microglia under the influence of GM-CSF that, in turn, is secreted by infiltrating T cells, (ii) CD11c ( cells then secrete proinflammatory cytokines (such as IL-12) and chemokines including CXCL13, CCL19 and CCL21; (iii) CXCL13, CCL19 and CCL21 act to recruit leukocytes to the CNS and help shape the cellular composition of perivascular infiltrates; (iv) local production of lymphoid chemokines also triggers lymphoid neogenesis (the development of lymph node-like structures) and B cell activation within the CNS; (v) ultimately, CNS lymphoid chemokines contribute to the severity and chronicity of clinical EAE. We will test each step of the above hypothetical scheme using novel experimental approaches.
In Aim 1 we will construct bone marrow chimeras with GFP-transgenic or GM-CSF deficient mice to determine the lineage of CNS CD11c ( cells.
In Aims 2 and 3, immunocompetent and lymphoid chemokine deficient mice will be compared with regard to susceptibility to adoptively transferred EAE, recruitment of leukocytes to white matter lesions, and lymphoid neogenesis and B cell activation within the CNS. Our studies might provide new insights into the pathogenesis of autoimmune demyelination and lead to innovative therapies such as reagents that antagonize lymphoid chemokines and/or block CNS dendritic cell accumulation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047687-02
Application #
6896551
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
2004-08-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$324,675
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Rainey-Barger, Emily K; Rumble, Julie M; Lalor, Stephen J et al. (2011) The lymphoid chemokine, CXCL13, is dispensable for the initial recruitment of B cells to the acutely inflamed central nervous system. Brain Behav Immun 25:922-31
King, Irah L; Kroenke, Mark A; Segal, Benjamin M (2010) GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization. J Exp Med 207:953-61
Lalor, Stephen J; Segal, Benjamin M (2010) Lymphoid chemokines in the CNS. J Neuroimmunol 224:56-61
Segal, Benjamin Matthew (2010) Th17 cells in autoimmune demyelinating disease. Semin Immunopathol 32:71-7
Kroenke, Mark A; Chensue, Stephen W; Segal, Benjamin M (2010) EAE mediated by a non-IFN-?/non-IL-17 pathway. Eur J Immunol 40:2340-8
Segal, Benjamin M (2009) Getting to the crux of the matter: IL-23 and Th17 cell accumulation in the CNS. Eur J Immunol 39:1713-5
King, Irah L; Dickendesher, Travis L; Segal, Benjamin M (2009) Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113:3190-7
Moravan, Michael; Segal, Benjamin M (2009) Treatment of CNS sarcoidosis with infliximab and mycophenolate mofetil. Neurology 72:337-40
Carlson, Thaddeus; Kroenke, Mark; Rao, Praveen et al. (2008) The Th17-ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease. J Exp Med 205:811-23
Kroenke, Mark A; Carlson, Thaddeus J; Andjelkovic, Anuska V et al. (2008) IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 205:1535-41

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