EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS--INHIBITION OF C

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Our goal in this study is to determine the role(s) complement plays in the cellular infiltration, inflammation and demyelination in experimental allergic encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). There is substantial evidence, in both MS and EAE, that complement is activated and may contribute to the inflammation and cellular destruction associated with these demyelinating diseases. There is also evidence, from our laboratory and others, that complement proteins and receptors are synthesized and expressed in the central nervous system (CNS), suggesting that local complement production may contribute to early disease development. One way to determine if complement contributes to the pathogenesis of demyelinating disease is to inhibit it's activation. Previous attempts to inhibit complement in EAE have demonstrated that strategy is feasible, but suffered from technical drawbacks. To overcome these limitations, we have developed a transgenic mouse model in which a soluble murine-specific inhibitor, sCrry, is produced by astrocytes using a glial fibrillary acidic protein (GFAP) promoter construct. We propose that blocking complement activation specifically in the CNS, using this new transgenic animal, provides a unique and better model system to determine the various roles that complement mediates in the development of the inflammatory response in EAE. We hypothesize that inhibiting complement activation using this model will reduce the cellular infiltration and demyelination, characteristic of EAE. In this application, we propose to 1) complete the analysis of our sCrry-expressing founder lines, 2) perform a kinetic analysis and comparison of clinical scores and histopathology of sCrry and control mice in EAE (extent and identification of infiltrating cell types, extent of demyelination and axonal transection), and 3) and assess altered gene expression in sCrry and control mice in EAE (correlation of transgene expression with clinical scores and histopathological features of the disease and examination of complement gene expression in vivo in relation to disease kinetics and severity). We believe the studies proposed in this application will generate significant new information on the role of complement in demyelinating disease. These studies will also provide the basis for future work examining the potential for complement-inhibiting biological reagents as therapeutic adjuvants in MS.