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Journal of Neurology
Published in: Journal of Neurology 5/2018

Open Access 01-05-2018 | Original Communication

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

Authors: Bryan Ceronie, Benjamin M. Jacobs, David Baker, Nicolas Dubuisson, Zhifeng Mao, Francesca Ammoscato, Helen Lock, Hilary J. Longhurst, Gavin Giovannoni, Klaus Schmierer

Published in: Journal of Neurology | Issue 5/2018

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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.
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Literature
1.
2.
Sefia E, Pryce G, Meier UC et al (2017) Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis. Mult Scler Relat Disord 14:46–50CrossRefPubMed
3.
van Oosten BW, Lai M, Hodgkinson S et al (1997) Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 49:351–357CrossRefPubMed
4.
Baker D, Marta M, Pryce G et al (2017) Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine 16:41–50CrossRefPubMedPubMedCentral
5.
Cohen JA, Coles AJ, Arnold DL et al (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380:1819–1828CrossRefPubMed
6.
Hauser SL, Bar-Or A, Comi G et al (2017) Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med 376:221–234CrossRefPubMed
7.
Giovannoni G, Comi G, Cook S et al (2010) A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 362:416–426CrossRefPubMed
8.
9.
Havrdova E, Arnold DL, Cohen JA et al (2017) Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology 89:1107–1116CrossRefPubMedPubMedCentral
10.
Wiendl H (2017) Cladribine—an old newcomer for pulsed immune reconstitution in MS. Nat Rev Neurol 13:573–574CrossRefPubMed
11.
Carson DA, Kaye J, Seegmiller JE (1977) Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: possible role of nucleoside kinase(s). Proc Natl Acad Sci USA 74:5677–5681CrossRefPubMedPubMedCentral
12.
Leist TP, Weissert R (2011) Cladribine: mode of action and implications for treatment of multiple sclerosis. Clin Neuropharmacol 34:28–35CrossRefPubMed
13.
Scheible H, Laisney M, Wimmer E et al (2013) Comparison of the in vitro and in vivo metabolism of cladribine (Leustatin, Movectro) in animals and human. Xenobiotica 43:1084–1094CrossRefPubMed
14.
Pakpoor J, Disanto G, Altmann DR et al (2015) No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm 2:e158CrossRefPubMedPubMedCentral
15.
Alvarez-Gonzalez C, Adams A, Mathews J et al (2017) Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis. Ann Clin Transl Neurol 4:506–511CrossRefPubMedPubMedCentral
16.
Baker D, Herrod SS, Alvarez-Gonzalez C et al (2017) Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm 4(4):e360CrossRefPubMedPubMedCentral
17.
Beutler E, Sipe JC, Romine JS et al (1996) The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA 93:1716–1720CrossRefPubMedPubMedCentral
18.
Baker D, Herrod SS, Alvarez-Gonzalez C et al (2017) Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of alemtuzumab. JAMA Neurol 74:961–969CrossRefPubMed
19.
Dooley J, Pauwels I, Franckaert D et al (2016) Immunologic profiles of multiple sclerosis treatments reveal shared early B cell alterations. Neurol Neuroimmunol Neuroinflamm 3:e240CrossRefPubMedPubMedCentral
20.
Laugel B, Borlat F, Galibert L et al (2011) Cladribine inhibits cytokine secretion by T cells independently of deoxycytidine kinase activity. J Neuroimmunol 240–241:52–57CrossRefPubMed
21.
Uhlén M, Fagerberg L, Hallström BM et al (2015) Tissue-based map of the human proteome. Science 347:1260419CrossRefPubMed
22.
23.
24.
Palanichamy A, Jahn S, Nickles D et al (2014) Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol 193:580–586CrossRefPubMedPubMedCentral
25.
Massaia M, Ma DD, Sylwestrowicz TA et al (1982) Enzymes of purine metabolism in human peripheral lymphocyte subpopulations. Clin Exp Immunol 50:148–154PubMedPubMedCentral
26.
Hunsucker SA, Mitchell BS, Spychala J (2005) The 5′-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther 107:1–30CrossRefPubMed
27.
Eggers EL, Michel BA, Wu H et al (2017) Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients. JCI Insight 2:92724CrossRefPubMed
28.
Anolik JH, Barnard J, Owen T et al (2007) Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis Rheum 56:3044–3056CrossRefPubMed
29.
Kim SH, Huh SY, Lee SJ et al (2013) A 5 year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol 70:1110–1117CrossRefPubMed
30.
Lebrun C, Bourg V, Bresch S et al (2016) Therapeutic target of memory B cells depletion helps to tailor administration frequency of rituximab in myasthenia gravis. J Neuroimmunol 298:79–81CrossRefPubMed
31.
Liliemark J, Albertioni F, Hassan M et al (1992) On the bioavailability of oral and subcutaneous 2-chloro-2′-deoxyadenosine in humans: alternative routes of administration. J Clin Oncol 10:1514–1518CrossRefPubMed
32.
Górski A, Grieb P, Korczak-Kowalska G et al (1993) Cladribine (2-chloro-deoxyadenosine, CDA): an inhibitor of human B and T cell activation in vitro. Immunopharmacology 26:197–202CrossRefPubMed
33.
Willis M, Pearson O, Illes Z, Sejbaek T et al (2017) An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 4:e320CrossRefPubMedPubMedCentral
34.
Mamani-Matsuda M, Cosma A, Weller S et al (2008) The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells. Blood 111:4653–4659CrossRefPubMed
35.
Szondy Z (1995) The 2-chlorodeoxyadenosine-induced cell death signalling pathway in human thymocytes is different from that induced by 2-chloroadenosine. Biochem J 311:585–588CrossRefPubMedPubMedCentral
36.
Ascherio A, Munger KL (2015) EBV and autoimmunity. Curr Top Microbiol Immunol 390:365–385PubMed
37.
Schwarz A, Balint B, Korporal-Kuhnke M et al (2016) B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 4:e309CrossRefPubMedPubMedCentral
38.
Lisak RP, Nedelkoska L, Benjamins JA et al (2017) B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro. J Neuroimmunol 309:88–99CrossRefPubMed
39.
Rastellj J, Hömig-Hölzel C, Seagal J et al (2008) LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1. Blood 111:1448–1455CrossRef
Metadata
Title
Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells
Authors
Bryan Ceronie
Benjamin M. Jacobs
David Baker
Nicolas Dubuisson
Zhifeng Mao
Francesca Ammoscato
Helen Lock
Hilary J. Longhurst
Gavin Giovannoni
Klaus Schmierer
Publication date
01-05-2018
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 5/2018
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-018-8830-y

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