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.
Recent clinical trials have established B cell depletion by the anti-CD20
chimeric antibody Rituximab as a beneficial therapy for patients with
relapsing-remitting multiple sclerosis (MS). The impact of Rituximab on T cell
responses remains largely unexplored. In the experimental autoimmune
encephalomyelitis (EAE) model of MS in mice that express human CD20, Rituximab
administration rapidly depleted peripheral B cells and strongly reduced EAE
severity. B cell depletion was also associated with diminished Delayed Type
Hypersensitivity (DTH) and a reduction in T cell proliferation and IL-17
production during recall immune response experiments. While Rituximab is not
considered a broad immunosuppressant, our results indicate a role for B cells as
a therapeutic cellular target in regulating encephalitogenic T cell responses in
specific tissues.
T cell co-stimulation through the CD28 receptor on T cells is critical to the induction of experimental autoimmune encephalomyelitis (EAE). In this study, expression of the co-stimulatory ligands B7-1 (CD80) and B7-2 (CD86), as well as the receptors CD28 and CTLA-4, were quantitated in central nervous system (CNS) tissues from mice at various stages of EAE. Immunohistochemistry and flow cytometry of CNS-infiltrating cells revealed a high percentage of infiltrating T cells expressing B7-1 and B7-2 during acute, chronic and relapsing EAE. Of the infiltrating cells 10-20% were CTLA-4(+), most of which were CD4(+) T cells. B7-1 and B7-2 expression within the CNS during active EAE might increase the potential for local activation of autoimmune T cells; however, the high level of expression of B7 molecules may also provide a mechanism for the autoregulation of activated CTLA-4(+) T cells.
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