Humanized mouse model of Rasmussen’s encephalitis supports the immune-mediated hypothesis
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
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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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 2

Cytokine production by hCD4+ and hCD8+ T lymphocytes infiltrating the CNS of control-NSG and RE-NSG animals.

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Cytokine production by hCD4+ and hCD8+ T lymphocytes infiltrating the CN...
(A) Double immunofluorescence labeling for hCD4+ (green) and hCD8+ (red) T lymphocytes in the brains of RE-NSG mice 5 weeks after transfer. Scale bars: 30 μm. (B) Percentage of hCD4+ (clear bar) and hCD8+ (solid bar) T lymphocytes in the brains of RE-NSG mice, as assessed by flow cytometry. Data represent the mean ± SEM. n = 6 mice. (C) Representative FACS dot plot and (D) kinetics of CNS infiltration by hCD4+ or hCD8+ cells expressing IFN-γ and IL-17 in NSG animals engrafted with PBMCs from RE patients (black bars) or control donors (white bars). Data represent the mean ± SEM of absolute numbers of immune cells. n = 4–6 animals per time point and 2–3 human PBMC donors. *P < 0.05 and **P < 0.01, by unpaired, 2-tailed Student’s t test with Holm-Sidak correction. (E) Confocal photomicrographs showing staining for hCD8 (red) and granzyme B (GzB, green) in the brains of control-NSG or RE-NSG mice. Images are representative of 7 fields from 6 sections obtained from 3 animals per group. Scale bar: 30 μm. Inset shows ×2 magnification of the indicated area. (F) Fluorescence intensity for HLA-DR and quantification of hCD11c+ cells in the CNS of control-NSG and RE-NSG mice. Data represent the mean ± SEM and are representative of 6 to 10 fields taken out of 6 sections from 3 animals per group. **P < 0.01, by unpaired, 2-tailed Student’s t test.