Abstract
Acute hemorrhagic leukoencephalomyelitis (AHLE) is a rare neurological condition characterized by the development of acute hemorrhagic demyelination and high mortality. The pathomechanism of AHLE, as well as potential therapeutic approaches, have remained elusive due to the lack of suitable animal models. We report the first murine model of AHLE using a variation of the Theiler's Murine Encephalitis Virus (TMEV) MS model. During acute TMEV infection, C57BL/6 mice do not normally undergo demyelination. However, when 7 day TMEV infected C57BL/6 mice are intravenously administered the immunodominant CD8 T cell peptide, VP2121–130, animals develop characteristics of human AHLE based on pathologic, MRI and clinical features including microhemorrhages, increased blood-brain barrier permeability, and demyelination. The animals also develop severe disability as assessed using the rotarod assay. This study demonstrates the development of hemorrhagic demyelination in TMEV infected C57BL/6 mice within 24 hours of inducing this condition through intravenous administration of CD8 T cell restricted peptide. This study is also the first demonstration of rapid demyelination in a TMEV resistant non-demyelinating strain without transgenic alterations or pharmacologically induced immunosuppression.
Highlights
The acute monophasic demyelinating disorders, including acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) usually present 1–3 weeks after infections or vaccination, but have been observed without preceding illness [1,2]
AHLE is associated with rapidly deteriorating focal and diffuse neurological symptoms leading to death within 2–14 days [5,6,7,8]
Its high mortality and poor response to therapy necessitate the development of animal models of AHLE to understand the mechanism of its pathology
Summary
The acute monophasic demyelinating disorders, including acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) usually present 1–3 weeks after infections or vaccination, but have been observed without preceding illness [1,2]. We have previously reported that a rapidly fatal hemorrhagic CNS disease develops in the C57BL/6 strain when the immunodominant VP2121–130 peptide is intravenously administered 7 days post TMEV infection [11]. Gadolinium-enhanced T1 weighted MRI showed evidence of BBB disruption in these same areas of the brain (F) These experiments demonstrated the presence of CD8 T cells in the corpus callosum, a region with high levels of demyelination and BBB permeability. We report that immunodominant peptide injection in TMEV infected C57BL/6 mice causes significant blood brain barrier (BBB) permeability and CNS damage, resulting in inflammatory infiltrates, microhemor-. Future experiments directed at putative mechanisms of BBB disruption and demyelination are already underway in our labs
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