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 sclerosis (MS), and in the rodent model of MS, experimental autoimmune encephalomyelitis (EAE), remain to be elucidated. To clarify the involvement of OLG death 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 were resistant to tumor necrosis factor-alpha-, anti-Fas antibody- and interferon-gamma-induced cell death. cre/p35 transgenic mice were resistant to EAE induction by immunization with the myelin oligodendrocyte glycoprotein. The numbers of infiltrating T cells and macrophages/microglia in the EAE lesions were significantly reduced, as were the numbers of apoptotic OLGs expressing the activated form of caspase-3. Thus, inhibition of apoptosis in OLGs by p35 expression alleviated the severity of the neurological manifestations observed in autoimmune demyelinating diseases.
Hisahara
S
S
Division of Transgenic Technology, Center for Animal Resources and Development (CARD), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Araki
T
T
Sugiyama
F
F
Yagami
K i
Ki
Suzuki
M
M
Abe
K
K
Yamamura
K
K
Miyazaki
J
J
Momoi
T
T
Saruta
T
T
Bernard
C C
CC
Okano
H
H
Miura
M
M
D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D020278:Demyelinating Autoimmune Diseases, CNS / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000378:metabolism; D015870:Gene Expression; D018390:Gene Targeting; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000235:genetics*; D019014:fas Receptor / Q000494:pharmacology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019014:fas Receptor; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D007371:Interferon-gamma