Much of our current understanding of immune mechanisms underlying multiple sclerosis (MS) comes from studies of experimental autoimmune encephalomyelitis (EAE) in mice. In 1 form of the model, immunization with the 35-55 peptide of myelin oligodendrocyte glycoprotein (MOG) induces chronic progressive disease with many manifestations of MS. Recently, we found that following MOG 35-55 immunization, mice deficient in decay accelerating factor (DAF), an intrinsic cell surface regulator previously thought to exclusively control complement C3/C5 convertases, develop dramatically more severe EAE than wild type (WT) controls. Clinical scores are markedly higher, lymphocyte infiltration and demyelination in dorsal columns are profoundly increased, and in cell-mediated immune assays, CD4+ T cells show 8-fold stronger MOG 35-55 recall responses as assessed both by proliferation and IFN-gamma ELISPOT assays. Prompted by this result, we studied DAF's effect both in vitro and in vivo on the induction of T cell immune reactivity, and unexpectedly found that it possesses potent inhibitory activity via effects both on antigen presenting cells (APCs) and responder CD4+ and CD8+ cells. In recent work we have found that 1) autoreactivity in MOG 35-55 induced EAE extends to proteolipid protein (PLP) and 2) mice doubly deficient in DAF and CD59, a related intrinsic complement inhibitor that works together with DAF, develop even more severe disease than DAF deficient mice. Some studies have shown that, in addition to T cell reactivity, complement participates in EAE pathogenesis, and a recent study has reported that CD59 protects against disease induced with whole MOG protein. Whether DAF's and CD59's protective effects in EAE are mediated via T cell inhibition, complement inhibition, or both is not established. Nevertheless, in view of our new findings of DAF's function as a T cell activation inhibitor as well as a complement inhibitor, and potentially similar effects of CD59, engineered recombinant DAF or CD59 could, in principle, constitute new therapeutic approaches for treating MS. In the proposed research we will 1) determine the extent to which deficiency of CD59 affects anti-myelin T cell autoreactivity as well as complement attack in both MOG 35-55-and PLP-induced EAE, 2) determine the cellular site(s) at which DAF (and CD59 if found) are exerting immune inhibitory activity, and, based on 1) and 2) develop appropriately targeted DAF (and/or CD59) therapeutic agents and test their abilities to ameliorate disease.
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