In this proposal, we will study the immune response responsible for a unique form of experimental allergic encephalomyelitis (EAE) in a nonhuman primate. Following immunization with whole white matter in adjuvant, Callithrix jacchus (C. jacchus) marmosets develop a relapsing-remitting disease and prominent acute and chronic demyelination closely resembling human multiple sclerosis (MS). In the initial funding period, we have found that the MS-like lesion appears to result from a complex immune response requiring both encephalitogenic T-cells and pathogenic antibody. T-cells reactive against myelin basic protein (MBP) are capable of mediating the inflammatory component of marmoset EAE. Demyelination, on the other hand, is antibody mediated. We have also found that the quantitatively minor myelin protein, myelin oligodendrocyte glycoprotein (MOG), is an important antigen in this system, as immunization against MOG or passive transfer of anti-MOG antibody reproduces the core features of the disease. We propose to utilize a number of state-of-the-art technologies to fully characterize the cellular and humoral immune response against MOG in C. jacchus, to study the role of determinant spreading in chronic disease, and to identify the antigen targets of demyelinating antibody and the mechanisms of antibody mediated demyelination. These studies will provide a foundation for immunotherapy based upon an understanding of the antigens and the immune mechanisms responsible for a complex autoimmune disease. ? ? MS affects approximately 350,000 Americans and is thus, excluding trauma, the most important acquired neurologic disease arising in early- to mid-adulthood. Because MS affects women more often than men, it is a particularly significant women's health problem. It is essential that useful model systems for this disabling disease be developed and studied. Advantages of the C. jacchus model for the study of MS include its clinical and pathologic similarity to MS, the natural chimerism of marmosets that permits adoptive transfer of T-cells, and the extensive conservation of immune and nervous system genes and proteins between human and nonhuman primate species. Equally important, work to date in C. jacchus has found that a diverse immune response to more than one antigen appears to be responsible for the MS-like lesion, a finding that parallels emerging concepts of the pathogenesis of human MS. ? ?
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