Our research has recently focused on the modeling of human multiple sclerosis (MS) using a novel model of experimental allergic encephalomyelitis (EAE) in a small New World primate, the common marmoset Callithrix jacchus (C. jacchus). When immunized with white matter in adjuvant, these monkeys develop a unique, primary demyelinating relapsing remitting disease that closely parallels clinical and neuropathologic characteristics of human MS. Similar to human MS, the T-cell responses against major myelin antigen, for example myelin basic protein (MBP), are diverse in terms of epitope recognition. Using strategies of immunization with purified, selective antigens of myelin and adoptive transfer, we have shown that the MS-like lesion in these nonhuman primates results from a complex immune response directed against more than one antigen of myelin. T-cells reactive against MBP are capable of mediating the inflammatory component of C. jacchus EAE. Demyelination however, is antibody mediated. A critical role for a minor constituent of myelin, myelin oligodendrocyte glycoprotein (MOG) has been demonstrated in this model. The importance of this unabundant protein (<0.05% of total myelin protein by weight) may be related to its highly immunogenic properties and/or to its predominant expression at the outermost surface of the myelin lamellae, where it is easily targeted by demyelinating antibody. Our research efforts will in the future focus on further definition of the immune responses (antibody and T-cells) against MOG in this model, development of strategies for induction of immunological tolerance to MOG, and definition of the role of complement-and antibody dependent- mediated mechanisms of cytotoxicity to oligodendrocyte, the myelin producing cells. This work in nonhuman primates will most likely provide a substantial amount of information that cannot be derived from rodent models of EAE. Many therapies are efficient in EAE but not in MS, and conversely, interspecies differences limit the usefulness of rodent models for the testing of novel treatments (for example interferon beta). We have already successfully employed the marmoset model in evaluating the efficacy of rolipram, a potent inhibitor of the type IV phosphodiesterase which suppresses the release of tumor necrosis factor-` by monocytes and macrophages. In a blinded clinical trial, administration of rolipram beginning 7 days after induction of EAE efficiently suppressed clinical, biological and radiological (magnetic resonance imaging) indices of disease, and abrogated demyelination. Because of the degree of similarity between C. jacchus EAE and human MS, this cytokine-based approach may well be a reasonable alternative for the treatment of the human disorder. Further exploration of the emerging concept that disease in both C. jacchus EAE and humans arise from a complex immune response that may be directed against many autoantigens will accelerate our current understanding of the pathophysiology of MS and facilitate the development of specific immunotherapies for demyelianting autoimmune diseases.
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