Lymphoid Chemokines in Autoimmune Encephalomyelitis

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DESCRIPTION (provided by applicant): 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.