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

• Published in: The Journal of clinical investigation Vol. 128; no. 5; pp. 2000 - 2009
• Main Authors: Kebir, Hania, Carmant, Lionel, Fontaine, François, Béland, Kathie, Bosoi, Ciprian M., Sanon, Nathalie T., Alvarez, Jorge I., Desgent, Sébastien, Pittet, Camille L., Hébert, David, Langlois, Marie-Josée, Rébillard, Rose-Marie, Nguyen, Dang K., Cieuta-Walti, Cécile, Holmes, Gregory L., Goodkin, Howard P., Mytinger, John R., Connolly, Mary B., Prat, Alexandre, Haddad, Elie
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2018
• Subjects: Adolescent; Adult; Animals; Atrophy; Biomedical research; Blood; Bone marrow; Brain - diagnostic imaging; Brain - immunology; Brain - physiopathology; Brain research; Care and treatment; Central nervous system; Child; Cortex; Crohn's disease; Disease; Disease Models, Animal; EEG; Electroencephalography; Encephalitis; Encephalitis - diagnostic imaging; Encephalitis - immunology; Encephalitis - physiopathology; Epilepsy; Female; Genetic aspects; Gliosis; Granzyme B; Hemispherectomy; Heterografts; Humans; Immune system; Immunodeficiency; Immunoglobulins; Inflammation - diagnostic imaging; Inflammation - immunology; Inflammation - physiopathology; Inflammatory bowel diseases; Inflammatory diseases; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - transplantation; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Mice; Middle Aged; Multiple sclerosis; Neurological diseases; Neurology; Pathology; Patients; Peripheral blood mononuclear cells; Risk factors; Rodents; Seizures; Seizures - diagnostic imaging; Seizures - immunology; Seizures - physiopathology; Transplants & implants; Viral infections; γ-Interferon; Neuroscience; Immunology; Mouse models; Immunotherapy; Neurological disorders
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI97098

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.