This competing renewal application is for funds to investigate the mechanism by which the demyelinated lesion (plaque) of multiple sclerosis (MS) is contained and prevented from spreading throughout the entire white matter. Typically, MS is a chronic progressive neurologic disorder with a prolonged clinical course often punctuated by relapses and remissions. Within the central nervous system (CNS), plaques tend to become histologically silent with time and develop sharp edges where the demyelinated lesions about myelinated white matter. These appearances suggest that the process of demyelination is actively down-regulated and that mechanisms are in place to prevent the lesion edge from expanding. The present proposal tests the hypothesis that in the CNS in MS, natural regulatory genes exist that function to protect adjacent unaffected white matter from potentially harmful immune mediators and thereby serve to contain the lesion area. The approach is novel and involves sets of experiments on CNS tissue from MS subjects and from animals with experimental autoimmune encephalomyelitis (EAE), a model for MS. To these CNS tissues, state-of-the-art neuropathology will be applied using immunologic and molecular probes to investigate cytokine and apoptotic gene expression.
Four specific aims will investigate whether structural changes and molecules occur to suggest that control mechanisms are present at the edge of demyelinated lesions.
These aims comprise a) experiments on chronic MS lesions to demonstrate that lesion containment involves clearance of oligodendrocytes by apoptosis and the localized expression of regulatory cytokines (e.g. IL-4, IL-10, TGFbeta1); b) experiments on a new model of adoptive EAE in developing mice to show that lymphocytes re cleared from the CNS by apoptosis and that glial cells express regulatory cytokines; c) experiments on CNS tissues from MS and EAE to show that the pro-apoptotic proinflammatory cytokines, tumor necrosis factor (TNFalpha) and lymphotoxin contribute to lesion development and that inhibition of such cytokines in EAE restricts lesion expansion; and d) a neuropathologic and immunocytochemical analysis of th CNS of GFAP knockout mice to examine whether an altered astroglial cell phenotype affects the development and establishment of inflammatory demyelinating lesions. The demonstration and understanding of natural immunoregulatory mechanisms operative during immune-mediated demyelination are of considerable significance to MS in which cytokine-related therapy is currently under intensive investigation.
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