Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination

The mechanisms underlying oligodendrocyte (OLG) loss and the precise roles played by OLG death in human demyelinating diseases such as multiple sclero sis (MS), and in the rodent model of MS, experimental autoimmune encephalom yelitis (EAE), remain to be elucidated. To clarify the involvement of OLG d eath in EAE, we have generated transgenic mice that express the baculovirus anti-apoptotic protein p35 in OLGs through the Cre-loxP system. OLGs from cre/p35 transgenic mice mere resistant to tumor necrosis factor-alpha-, ant i-Fas antibody- and interferon-gamma-induced cell death. cre/p35 transgenic mice mere resistant to EAE induction by immunization with the myelin oligo dendrocyte glycoprotein, The numbers of infiltrating T cells and macrophage s/microglia in the EAE lesions were significantly reduced, as were the numb ers of apoptotic OLGs expressing the activated form of caspase-3. Thus, inh ibition of apoptosis in OLGs by p35 expression alleviated the severity of t he neurological manifestations observed in autoimmune demyelinating disease s.