Journal
ARCHIVES OF NEUROLOGY
Volume 67, Issue 6, Pages 707-714Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/archneurol.2010.99
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Funding
- National Institutes of Health (NIH) (NINDS) [PO1 NS059560- 01]
- NINDS [UO1 NS45719-01A1, RO1 NS047592]
- NINDS/National MS Society [RO1 NS 051591, NMSS RG 3915-A-15]
- National MS Society [RG3982, FG 1665-A-1]
- Acorda Therapeutics
- NIH [K23NS052430-01A1, K12RR02324902, K24RR017100, 5UL1 RR024992]
- Washington University
- Pfizer
- DANA Foundation
- National MS Society USA [RG 3292]
- Barnes-Jewish Hospital Foundation
- Genentech, Inc
- Biogen Idec
- Manny and Rosalyn Rosenthal-Dr John L. Trotter Chair in Neuroimmunology
- Hoffman-La Roche
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Background: B cells are implicated in the pathogenesis of multiple sclerosis. A beneficial effect of B-cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear. Objective: To determine the relationship between T and B cells and changes in cerebrospinal fluid (CSF) chemokine levels with rituximab, a monoclonal antibody that targets CD20. Design: Phase 2 trial of rituximab as an add-on therapy. Setting: The John L. Trotter Multiple Sclerosis Center, Washington University. Participants and Intervention: Thirty subjects who had relapsing-remitting multiple sclerosis with clinical and magnetic resonance imaging activity despite treatment with an immunomodulatory drug received 4 weekly doses of rituximab (375 mg/m(2)). Main Outcome Measures: Lumbar puncture was performed before and after rituximab infusions in 26 subjects. Levels of B and T lymphocytes in the CSF were enumerated by flow cytometry, and chemoattractant levels were measured by enzyme-linked immunosorbent assay. Results: After rituximab administration, CSF B-cell levels were decreased or undetectable in all subjects, and CSF T-cell levels were reduced in 21 subjects (81%). The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 levels decreased (P = .002 and P = .03, respectively). The proportional decline in CSF T-cell levels correlated with the proportional decrease in CXCL13 levels (r = 0.45; P = .03), suggesting a possible relationship. The CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment. Conclusions: In subjects with multiple sclerosis, B cells are critical for T-cell trafficking into the central nervous system and may alter the process by influencing chemokine production within the central nervous system.
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