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  • The EMBO Journal (2000) 19, 341 - 348
  • doi:10.1093/emboj/19.3.341

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

Shin Hisahara1, Takashi Araki2, Fumihiro Sugiyama3, Ken-ichi Yagami3, Misao Suzuki4, Kuniya Abe5, Ken-ichi Yamamura4,5, Jun-ichi Miyazaki6, Takashi Momoi7, Takao Saruta2, Claude C. A. Bernard8, Hideyuki Okano1,9 and Masayuki Miura1,9

  1. Division of Neuroanatomy, Department of Neuroscience, Biomedical Research Center (D-12), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
  2. Department of Nephrology, Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8532, Japan
  3. Laboratory Animal Research Center, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan
  4. Division of Transgenic Technology, Center for Animal Resources and Development (CARD), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
  5. Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, 4-24-1 Kuhonji, Kumamoto 862-0976, Japan
  6. Department of Nutrition and Physiological Chemistry, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
  7. Division of Development and Differentiation, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan
  8. Neuroimmunology Laboratory, La Trobe University, Bundoora, Melbourne, 3083, Australia
  9. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Correspondence to:

Masayuki Miura, Corresponding author at: Division of Neuroanatomy, Department of Neuroscience, Biomedical Research Center (D-12), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan, E-mail: mmiura@nana.med.osaka-u.ac.jp

Received 11 October 1999; Accepted 2 December 1999; Revised 2 December 1999

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.

  • Keywords:

    • apoptosis,
    • baculovirus p35,
    • caspase,
    • demyelination,
    • oligodendrocyte