title: Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, for which there is currently no cure or effective treatment. In this disease, local neuroinflammation develops along the disease course and contributes to its rapid progression. In several models of CNS pathologies, circulating immune cells were shown to display an indispensable role in the resolution of the neuroinflammatory response. The recruitment of such cells to the CNS involves activation of the choroid plexus (CP) of the brain for leukocyte trafficking, through a mechanism that requires IFN-γ signaling. Here, we found that in the mutant SOD1(G93A) (mSOD1) mouse model of ALS, the CP does not support leukocyte trafficking during disease progression, due to a local reduction in IFN-γ levels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3(+) regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma. The immunization resulted in the attenuation of disease progression and an increased life expectancy of the mSOD1 mice. Collectively, our results demonstrate that recruitment of immunoregulatory cells to the diseased spinal cord in ALS, needed for fighting off the pathology, can be enhanced by transiently boosting peripheral immunity to myelin antigens.
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gilad
authors.initials: G
authors.lastname: Kunis
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Kuti
authors.initials: K
authors.lastname: Baruch
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Omer
authors.initials: O
authors.lastname: Miller
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel Michal.Schwartz@weizmann.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Schwartz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology* / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002831:Choroid Plexus / Q000166:cytology* / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D007114:Immunization; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D061251:Primary Cell Culture; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: T cells; amyotrophic lateral sclerosis; autoimmunity; choroid plexus; neurodegeneration