Kurzfassung

In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, immunization with myelin antigens leads to demyelination and paralysis. Members of the TNF/TNF-R superfamily were reported to be important in the T helper cell mediated apoptosis of oligodendrocytes (ODCs). We have recently demonstrated that expression of Fas and TNF-R1 pro-apoptotic receptors by glia cells, in particular oligodendrocytes (ODC) is critical for disease induction.
In the present...In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, immunization with myelin antigens leads to demyelination and paralysis. Members of the TNF/TNF-R superfamily were reported to be important in the T helper cell mediated apoptosis of oligodendrocytes (ODCs). We have recently demonstrated that expression of Fas and TNF-R1 pro-apoptotic receptors by glia cells, in particular oligodendrocytes (ODC) is critical for disease induction.
In the present application we suggest to further analyze the role of pro-apoptotic and inflammatory signals for EAE induction and development. By means of conditional gene targeting we will delete Fas in astrocytes, to investigate their role in EAE. To better clarify the role of apoptotic signals in ODCs during EAE, we will make use of mice where a common mediator of apoptosis, Caspase-8, will be deleted in ODCs.
Further more, to better understand the initial inflammatory signals in the disease, we will delete the two receptors for IL-6, gp130 and IL-6b chain in ODCs, astrocytes and the whole central nervous system. To better characterize the initial inflammatory signal medicated in the CNS, we will also generate mice that lack a newly described inhibitor of NFkB, CYLD-1. Together, we will use a verity of mice that lack receptors or mediators of apoptotic and
inflammatory signals, to better understand the signals that lead to EAE induction and development.
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