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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

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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 5

Effect of prophylactic treatment with anti–α4 integrin antibody on the development of disease in RE-NSG mice.

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Effect of prophylactic treatment with anti–α4 integrin antibody on the d...
RE-NSG mice were treated with isotype control (black circles) or anti–α4 antibody (gray circles) in a prophylactic setting. The effect of α4 integrin blockade was assessed for (A and B) the infiltration of hCD45+ and GFAP in the brains of RE-NSG mice, (C and D) the expression of HLA-DR, and (E) the occurrence of seizures. Arrowheads point to the few hCD45 cells detected in the brains of RE-SNG mice treated with anti-α4 integrin antibody. Images are representative of 6 to 11 fields from 4 sections obtained from 2 to 4 animals per group. Scale bars: 30 μm. Data shown in E are expressed as the mean ± SEM. **P < 0.01 and ***P < 0.001, by unpaired, 2-tailed Student’s t test (B and D) and χ2 test (E).
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