Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is considered to be immune-mediated. A pivotal question in the disease process is how cells of the immune system target and invade the CNS. The accumulation of leukocytes at sites of inflammation involves the complex interaction of cytokines, chemotactic factors and growth factors that regulate homing, adhesion, migration and retention at the target site. Recently, considerable interest has focused on the contribution of small, inducible cytokines, the chemokines, to the overall process. Chemokines represent early response genes to inflammatory mediators and are themselves strongly pre- inflammatory. Included in the chemokine-Beta family are two closely related proteins macrophage inflammatory peptide MIP-1alpha and MIP- 1Beta, the macrophage chemoattractant-peptide-1 (MCP-1), and RANTES. In macrophages, MIP-1alpha and MIP-1Beta are rapidly induced to high levels by the Th1 cytokine IFNgamma. In experimental allergic encephalomyelitis (EAE), an animal model of MS, we showed significant induction of the chemokine MCP-1, the kinetics and levels of which closely paralleled CNS macrophage invasion and clinical expression of disease. To build on these studies and to explore further the contribution of macrophages to the inflammatory demyelinating diseases, we now propose to investigate the contribution of members of the chemokine-beta family to inflammation in the CNS.
In specific aim 1, the expression of chemokines will be examined in immune-mediated and trauma-induced CNS inflammation and will examine the role of the interaction of the encephalitogenic T cell with its APC in chemokine production.
Specific aim 2 will examine how chemokines amplify the inflammatory process.
Specific aim 3 will study possible mechanisms involved in cytokine-mediated regulation of these events.
Specific aim 4 will test if depletion of these factors alters disease expression.
Specific aim 5 will assess their expression in tissues from patients with MS and suitable controls. The long-term objectives of this study are to define the mechanisms involved in CNS inflammation with the hope that alternative modes of intervention can be devised that will control access of inflammatory cells to the CNS.
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