Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells
(2018) Journal of neurology — Vol. 265, n° 5, p. 1199-1209 (2018)
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- Authors
Baker, David 
- Abstract
- The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories. Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3 T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5' nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells. Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.
- Affiliations
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
Citations
Ceronie, B., Jacobs, B. M., Baker, D., Dubuisson, N., Mao, Z., Ammoscato, F., Lock, H., Longhurst, H. J., Giovannoni, G., & Schmierer, K. (2018). Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. Journal of neurology, 265(5), 1199-1209. https://doi.org/10.1007/s00415-018-8830-y (Original work published 2018)