TARGETED CNS EXPRESSION OF INTERFERON-GAMMA IN TRANSGENIC MICE LEADS TO HYPOMYELINATION, REACTIVE GLIOSIS, AND ABNORMAL CEREBELLAR DEVELOPMENT

Circumstantial and experimental evidence has implicated the immune cyt okine interferon-gamma (IFN-gamma) as a key mediator in the pathologic al changes that are observed in many demyelinating disorders, includin g the most common human demyelinating disease, multiple sclerosis. To produce an animal model with which to study the effects of IFN-gamma o n the CNS, we have generated transgenic mice in which the expression o f IFN-gamma has been placed under the transcriptional control of the m yelin basic protein (MBP) gene. Transgenic mice generated with this co nstruct have a shaking/shivering phenotype that is similar to that obs erved in naturally occurring mouse models of hypomyelination (e.g., sh iverer, jimpy, quaking), and these transgenic animals have dramaticall y less CNS myelin than control animals. Reactive gliosis and increased macrophage/microglial F4/80 immunostaining were also observed. Additi onally major histocompatibility complex (MHC) class I and class II mRN A levels were increased in the CNS of MBP/IFN-gamma transgenic mice, a nd the increase in MHC class I mRNA expression was detected in both wh ite and gray matter regions. Furthermore, cerebellar granule cell migr ation was abnormal in these animals. These results strongly support th e hypothesis that IFN-gamma is a key effector molecule in immune-media ted demyelinating disorders and indicate that the presence of this cyt okine in the CNS may also disrupt the developing nervous system.