Horwitz Marc S, Evans Claire F, Mcgavern Dorian B, Rodriguez Moses, Oldstone Michael B A
Departments of Immunology (IMM-23), 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Neuropharmacology, the Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nat Med. 1997 Sep;3(9):1037-1041. doi: 10.1038/nm0997-1037.
Ever since the use of interferon-gamma to treat patients with multiple sclerosis resulted in enhanced disease, the role of IFN-gamma in demyelination has been under question. To address this issue directly, transgenic mice were generated that expressed the cDNA of murine IFN-gamma in the central nervous system by using an oligodendrocyte-specific promoter. Expression of the transgene occurred after 8 weeks of age, at which time the murine immune and central nervous systems are both fully developed. Directly associated with transgene expression, primary demyelination occurred and was accompanied by clinical abnormalities consistent with CNS disorders. Additionally, multiple hallmarks of immune-mediated CNS disease were observed including upregulation of MHC molecules, gliosis and lymphocytic infiltration. These results demonstrate a direct role for IFN-gamma as an inducer of CNS demyelination leading to disease and provide new opportunities for dissecting the mechanism of demyelination.
自从使用干扰素-γ治疗多发性硬化症患者导致疾病加重以来，干扰素-γ在脱髓鞘中的作用一直受到质疑。为了直接解决这个问题，通过使用少突胶质细胞特异性启动子，构建了在中枢神经系统中表达鼠干扰素-γ cDNA的转基因小鼠。转基因在8周龄后开始表达，此时小鼠的免疫系统和中枢神经系统均已完全发育。与转基因表达直接相关的是，出现了原发性脱髓鞘，并伴有与中枢神经系统疾病相符的临床异常。此外，还观察到免疫介导的中枢神经系统疾病的多个特征，包括MHC分子上调、胶质细胞增生和淋巴细胞浸润。这些结果证明了干扰素-γ作为导致疾病的中枢神经系统脱髓鞘诱导剂的直接作用，并为剖析脱髓鞘机制提供了新的机会。
