Cladribine exerts an immunomodulatory effect on human and murine dendritic cells

Kraus, Stefan H.P.; Luessi, Felix; Trinschek, Bettina; Lerch, Steffen; Hubo, Mario; Poisa-Beiro, Laura; Paterka, Magdalena; Jonuleit, Helmut; Zipp, Frauke; Jolivel, Valérie

doi:10.1016/j.intimp.2013.11.027

Cited by 32 publications

(23 citation statements)

References 59 publications

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“…Other properties displayed by the drug in vitro include immunomodulation [e.g. inhibition of T-cell activation/cytokine secretion [ 21 ], induction of a more anti-inflammatory cytokine response by peripheral blood mononuclear cells (PBMCs) [ 22 ] and reduction of inflammatory cytokine/chemokine secretion by dendritic cells [ 23 ]] and reduction of PBMC migration in a blood-brain-barrier model [ 24 ]. Cladribine also reduced serum levels of some soluble adhesion molecules (sICAM-1 and sE-Selectin, but not sVCAM-1) involved in regulating entry of inflammatory cells into the brain in MS patients [ 25 ] and had direct neuroprotective effects in a murine model of MS by interfering with the effects of interleukin-1β at synapses [ 20 ].…”

Section: Pharmacodynamic Properties Of Cladribinementioning

confidence: 99%

Cladribine Tablets: A Review in Relapsing MS

Deeks

2018

CNS Drugs

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Cladribine is a deoxyadenosine analogue prodrug that preferentially depletes lymphocytes, key cells underlying multiple sclerosis (MS) pathogenesis. Cladribine tablets (Mavenclad) represent the first short-course oral disease-modifying drug (DMD) for use in MS. The tablets, administered in two short courses 1 year apart, are indicated for the treatment of adults with highly active relapsing MS on the basis of data from pivotal clinical trials, including the phase 3 study CLARITY and its extension. A cumulative cladribine tablets dose of 3.5 mg/kg administered in this fashion in CLARITY reduced clinical relapse, disability progression and MRI-assessed disease activity and also improved some aspects of health-related quality of life (HR-QOL) versus placebo over 96 weeks in adults with relapsing-remitting MS (RRMS). Moreover, in the 96-week extension (plus 24 weeks' supplemental follow-up), no additional clinical benefit was gained from continuing versus discontinuing cladribine tablets after the first two annual courses of therapy, although MRI activity was more notable in a subset of cladribine tablet recipients who discontinued the drug. In post hoc analyses of CLARITY and/or a phase 2b trial, benefits of cladribine tablets were seen in patients with high disease activity (HDA) relapsing MS that were sometimes greater than in patients without HDA. Cladribine tablets have an acceptable tolerability profile and do not appear to be associated with an increased risk of overall infection or with an increased risk of malignancy (vs. matched reference populations). Active comparisons and longer-term follow-up would be beneficial, although current data indicate that for adults with highly active relapsing MS, cladribine tablets are an effective treatment option with the convenience of low-burden, short-course, oral administration.

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Section: Pharmacodynamic Properties Of Cladribinementioning

confidence: 99%

Cladribine Tablets: A Review in Relapsing MS

Deeks

2018

CNS Drugs

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“…Cladribine targets lymphocytes, which are dependent on adenosine deaminase to maintain equilibrium of triphosphorylated nucleotides. 5 Cladribine's therapeutic effect in multiple sclerosis is through a rapid and sustained depletion of CD4 and CD8 T cells with a less sustained effect on CD19 B cells. This occurs with a relative sparing of other immune cells such as neutrophils and monocytes.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Cladribine tablets and multiple sclerosis: NICE technology appraisal

Gaber¹,

Shippen²

2018

Prog Neurol Psychiatry

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Cladribine is the first disease modifying treatment (DMT) for relapsing remitting multiple sclerosis (RRMS) that progressed straight to a positive final recommendation in the NICE appraisal process. The final recommendations were published in December 2017.1 An agreement between NHS England and Merck, the manufacturer of cladribine (Mavenclad), will allow MS patients who are suffering from highly active or rapidly evolving RRMS to access the drug. Here, the authors discuss the clinical and economic considerations for cladribine usage.

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“…In a study of 50 pwMS, subcutaneous cladribine was associated with a rise in the plasmacytoid:myeloid dendritic cell ratio 58. In healthy human monocyte-derived DCs, cladribine reduced endocytosis of FITC-dextran 59. Interestingly, when murine DCs loaded with a MOG peptide were incubated with or without cladribine in the presence of MOG-specific naïve T cells, cladribine was associated with a higher proportion of T cells developing into IL-10-producing cells and a lower proportion developing into IFNγ and TNFα-producing cells.…”

Section: Introductionmentioning

confidence: 98%

“…Chemotaxis in vivo is partly dependent on chemokine signalling. Interestingly, cladribine incubation reduced the production of chemokines by monocyte-derived human DCs 59. There was a reduction in the amount MIP-1a, MIP-1b and MIG and a commensurate decrease in monocyte chemotaxis in vitro 59.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, cladribine incubation reduced the production of chemokines by monocyte-derived human DCs 59. There was a reduction in the amount MIP-1a, MIP-1b and MIG and a commensurate decrease in monocyte chemotaxis in vitro 59. Furthermore, in a study of 25 pwMS, cladribine treatment reduced serum and CSF levels of the chemokine RANTES while only reducing CSF, but not serum, IL-8 (a neutrophil chemoattractant) 63.…”

Section: Introductionmentioning

confidence: 99%

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Cladribine: mechanisms and mysteries in multiple sclerosis

Jacobs

Ammoscato

Giovannoni³

et al. 2018

J Neurol Neurosurg Psychiatry

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Cladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine's action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.

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Cladribine exerts an immunomodulatory effect on human and murine dendritic cells

Cited by 32 publications

References 59 publications

Cladribine Tablets: A Review in Relapsing MS

Cladribine Tablets: A Review in Relapsing MS

Cladribine tablets and multiple sclerosis: NICE technology appraisal

Cladribine: mechanisms and mysteries in multiple sclerosis

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