Inflammatory cell recruitment into the CNS is a critical step in the evolution of diverse pathological processes. Chemokines, pro-inflammatory cytokines that stimulate directional migration of specific subsets of leukocytes, appear to have remarkable potency as chemoattractants in the Central Nervous System (CNS). Chemokine expression, including that of monocyte chemoattractant protein-l (MCP-l), a chemoattractant for monocytes and T cells in vitro, has been found in diverse animal models of CNS disease including experimental autoimmune encephalomyelitis (EAE), a model of immune-mediated demyelinating disease resembling multiple sclerosis. In this proposal we will address the function of MCP-l in transgenic mice by expressing this chemokine under control of two well-characterized CNS-specific promoters which we predict will yield opposite target-cell responses. These mice will be examined in their native state as well as after stimulation with pro-inflammatory agents and induction of EAE to further define the role of MCP-1 in CNS inflammation.
The specific aims are as follows. 1) We will establish and characterize transgenic mice expressing MCP-l under control of the CNS-specific 2.2 kb human glial fibrillary acidic protein (GFAP) promoter in (SWxSJL) mice (GFAP/MCP-l TG mice) as a model of tissue-specific target-cell unresponsiveness to MCP-l. 2) We will establish and characterize transgenic mice expressing MCP-1 under control of the CNS-specific 1.9 kb myelin basic protein (MBP) promoter in (SWRxSJL) mice (MBP/MCP-l TG mice) as a model of MCP-l-induced monocyte recruitment into the CNS. 3. We will characterize clinical and histological features of EAE, a model of immune-mediated demyelinating disease, in these two models.
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