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J Neurol. 2018 May;265(5):1199-1209. doi: 10.1007/s00415-018-8830-y. Epub 2018 Mar 17.

Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.

Author information

1
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
2
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK. david.baker@qmul.ac.uk.
3
Haematology Unit, The Royal London Hospital, Barts Health NHS Trust, London, UK.
4
Emergency Care and Acute Medicine Clinical Academic Group Neuroscience, The Royal London Hospital, Barts Health NHS Trust, London, UK.

Abstract

BACKGROUND:

The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown.

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

B cell; Cladribine; Deoxycytidine kinase; Disease-modifying treatment; Memory B cells; Multiple sclerosis

PMID:
29550884
PMCID:
PMC5937883
DOI:
10.1007/s00415-018-8830-y
[Indexed for MEDLINE]
Free PMC Article

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