Humanized mouse model of Rasmussen’s encephalitis supports the immune-mediated hypothesis
Hania Kebir, … , Alexandre Prat, Elie Haddad
Hania Kebir, … , Alexandre Prat, Elie Haddad
Published April 9, 2018
Citation Information: J Clin Invest. 2018;128(5):2000-2009. https://doi.org/10.1172/JCI97098.
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Research Article Immunology Neuroscience

Humanized mouse model of Rasmussen’s encephalitis supports the immune-mediated hypothesis

Abstract

Rasmussen’s encephalitis (RE) is a chronic inflammatory brain disorder that causes frequent seizures and unilateral hemispheric atrophy with progressive neurological deficits. Hemispherectomy remains the only treatment that leads to seizure freedom for this refractory epileptic syndrome. The absence of an animal model of disease has been a major obstacle hampering the development of effective therapies. Here, we describe an experimental mouse model that shares several clinical and pathological features with the human disease. Immunodeficient mice injected with peripheral blood mononuclear cells from RE patients and monitored by video electroencephalography developed severe seizures of cortical origin and showed intense astrogliosis and accumulation of human IFN-γ– and granzyme B–expressing T lymphocytes in the brain compared with mice injected with immune cells from control subjects. We also provide evidence for the efficacy of α4 integrin blockade, an approved therapy for the treatment of multiple sclerosis and Crohn’s disease, in reducing inflammatory markers associated with RE in the CNS. This model holds promise as a valuable tool for understanding the pathology of RE and for developing patient-tailored experimental therapeutics.

Authors

Hania Kebir, Lionel Carmant, François Fontaine, Kathie Béland, Ciprian M. Bosoi, Nathalie T. Sanon, Jorge I. Alvarez, Sébastien Desgent, Camille L. Pittet, David Hébert, Marie-Josée Langlois, Rose-Marie Rébillard, Dang K. Nguyen, Cécile Cieuta-Walti, Gregory L. Holmes, Howard P. Goodkin, John R. Mytinger, Mary B. Connolly, Alexandre Prat, Elie Haddad

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Figure 3

Neuropathology in RE-NSG animals.

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Neuropathology in RE-NSG animals. (A) Confocal photomicrograph showing G...
(A) Confocal photomicrograph showing GFAP (red) and hCD45+ (green) in the CNS of control-NSG and RE-NSG mice 5 weeks after transfer. Scale bar: 30 μm; insets ×3 magnification. (B) Quantification of hCD45+ cells and staining intensity for GFAP in the CNS of control-NSG and RE-NSG mice. Data represent the mean ± SEM of 10 or more fields from 6 sections obtained from 3 animals per group. ***P < 0.001, by unpaired, 2-tailed Student’s t test. (C) Immunohistoperoxidase staining for APP in the hippocampal gyrus of control-NSG and RE-NSG mice 6 weeks after transfer. Arrowheads indicate APP+ neuronal cells. Scale bar: 30 μm. (D) Quantification of cell death marker TUNEL in the CNS of control-NSG and RE-NSG mice 6 weeks after transfer. Data are expressed as the mean ± SEM of 10 to 20 fields from 6 sections obtained from 2 animals per group. *P < 0.05, by unpaired, 2-tailed Student’s t test. (E) Immunofluorescence staining for hCD45 (green), cleaved caspase-3 (Cas-3, red), and NeuN (upper panels, white) or IB4 (lower panels, white) in the brains of RE-NSG mice. DAPI (blue) was used for nuclear staining. Images are representative of 7 fields from 3 sections obtained from 3 RE-NSG mice. Scale bars: 20 μm. The two upper left inset frames show ×1.33 magnification of the dashed boxed area. All other insets are magnified ×2.