Hisahara S, Araki T, Sugiyama F, Yagami K i, Suzuki M, Abe K, Yamamura K, Miyazaki J, Momoi T, Saruta T, Bernard C C, Okano H, Miura M
Division of Transgenic Technology, Center for Animal Resources and Development (CARD), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
EMBO J. 2000 Feb 1;19(3):341-8. doi: 10.1093/emboj/19.3.341.
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.
少突胶质细胞（OLG）丢失的潜在机制以及OLG死亡在人类脱髓鞘疾病如多发性硬化症（MS）和MS的啮齿动物模型实验性自身免疫性脑脊髓炎（EAE）中所起的精确作用，仍有待阐明。为了阐明OLG死亡在EAE中的作用，我们通过Cre-loxP系统构建了在OLG中表达杆状病毒抗凋亡蛋白p35的转基因小鼠。来自cre/p35转基因小鼠的OLG对肿瘤坏死因子-α、抗Fas抗体和干扰素-γ诱导的细胞死亡具有抗性。cre/p35转基因小鼠对用髓鞘少突胶质细胞糖蛋白免疫诱导的EAE具有抗性。EAE病变中浸润的T细胞和巨噬细胞/小胶质细胞数量显著减少，表达活化形式半胱天冬酶-3的凋亡OLG数量也减少。因此，通过p35表达抑制OLG凋亡可减轻自身免疫性脱髓鞘疾病中观察到的神经学表现的严重程度。
