Proteolipid protein (PLP) is a major component of myelin and appears to be a target of immune responses in both experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Chronic relapsing EAE is induced in SJL/J mice by immunization with intact PLP or the immunodominant epitope (PLP139-151). EAE can also be induced by the adoptive transfer of T-cells specific for either PLP or PLP139-151. A relapsing remitting course of disease follows that is characterized clinically by ascending paralysis that begins with loss of tail tone and eventually manifests itself as severe hind limb weakness. Histologically, perivascular mononuclear cell infiltrates of the central nervous system (CNS) white matter consisting of macrophages and lymphocytes are noted. Areas of acute and chronic demyelination can also be seen. Because of the similarities in histology and clinical disease with that seen in MS, EAE is considered an excellent animal model for human demyelinating diseases. Chemokines are small molecular weight cytokines that have chemotactic properties for leukocytes. Some chemokines such as macrophage inflammatory protein (MlP)-1a, MIP-1b, and monocyte chemotactic protein (MCP)-1 are preferentially chemotactic for Iymphocytes and macrophages. The investigators will address the role(s) of MlP-1, MIP-1b, and MCP-1 in the development of acute and relapsing EAE induced by either active immunization or adoptive transfer of PLP/PLP139-151-specific T-cells. This will include examining cell-specific, temporal chemokine (MlP-1a, MIP-1b and MCP-1) mRNA expression and protein production in the CNS as well as peripheral lymphoid sites; using in vivo antibody depletion of chemokines and assessing the effect on acute and relapsing EAE in terms of clinical and histological disease; and determining the role of chemokines on mononuclear cell subset infiltration into the CNS during the course of both acute and relapses of EAE. The role of chemokines in both the infiltration of PLP139-151-specific T-cells into the CNS and the peripheral immune T-cell response will be explored.
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