title: The effect of B-cell depletion in the Theiler's model of multiple sclerosis.
abstract: B cell depletion (BCD) is being considered as a treatment for multiple sclerosis (MS), but there are many uncertainties surrounding the use of this therapy, such as its potential effect in individuals with concurrent viral infections. We sought to discover what effect BCD, induced by an anti-CD20 monoclonal antibody, would have on Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Mice were injected with the anti-CD20 monoclonal antibody 5D2, 14 days before or 14 days after infection with TMEV. Efficacy of depletion of B cells was assessed by flow cytometry of CD19(+) cells. Mouse disability was measured by Rotarod, viral load was measured by real time PCR for TMEV RNA. Binding and neutralizing antibody levels were determined in sera and CSF by ELISA, and in CNS by real time PCR for IgG RNA. Inflammation, microglial activation, axonal damage and demyelination were assessed using immunohistochemistry. 5D2-induced BCD was confirmed by demonstration of nearly absent CD19(+) cells in the blood and lymphoid tissue. Systemic and CNS antibody responses were suppressed during 5D2 treatment. Higher viral loads were detected in 5D2-treated mice than in controls, and the viral levels correlated negatively with IgG production in the brain. Overall, 5D2 caused worsening of the early encephalitis and faster progression of disability, as well as exacerbation of the pathology of TMEV-IDD at the end stage of the disease. These data indicate that BCD in humans might worsen CNS viral infections and might not improve disability accrual in MS.
authors.affiliation: Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Electronic address: Francesca.Gilli@dartmouth.edu.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gilli
authors.affiliation: Department of Neurology, University of Medicine and Dentistry-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Libin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Campbell
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Department of Neurology, University of Medicine and Dentistry-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pachner
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects / Q000502:physiology; D018951:Antigens, CD20 / Q000276:immunology; D001402:B-Lymphocytes / Q000473:pathology*; D002490:Central Nervous System / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000473:pathology; D017945:Theilovirus / Q000472:pathogenicity*; D013997:Time Factors; D019562:Viral Load
chemical_list: D000906:Antibodies; D018951:Antigens, CD20; D007074:Immunoglobulin G
keywords: B cell depletion; Disability progression; Multiple sclerosis; TMEV-IDD