The Development of Rational Strategies for Selective Immunotherapy against Autoimmune Demyelinating Disease

Abstract

This chapter describes the strong parallels that exist between T cell receptor (TCR) usage in the pathogenesis of experimental allergic encephalomyelitis (EAE), and TCR usage in myelin basic protein (MBP)-specific T cells in the peripheral blood of MS patients and in T cells in demyelinative plaques in the MS brain. Based on these similarities, selective immunotherapy that targets either class II molecules of the major histocompatibility complex (MHC) or TCR-variable (TCR–V) regions is described in EAE, with consideration given to application of these principles in MS. These new therapeutic approaches involve monoclonal antibodies (Mabs) directed to either HLA class II molecules or TCR-V region molecules, or peptides that compete with HLA class II molecules or vaccination against TCR–V regions. Chronic EAE with relapses and remissions and with pathologic evidence of demyelination can be induced in mice with peptide fragments of MBP. Other peptide fragments of MBP are also immunogenic, but instead of inducing disease these fragments can protect mice from the induction of EAE caused by a pathogenic fragment. Highly selective therapies with antibodies or peptide directed against TCR or HLA class II molecules thus appear feasible for treatment of MS, especially because the elucidation of target TCR and HLA molecules is proceeding rapidly. It is worth noting that Teitelbaum and co-workers have treated EAE with a random copolymer (termed COPI) of tyrosine, alanine, lysine, and glutamate.