The development and impact of cladribine on lymphoid and myeloid cells in multiple sclerosis

Voo, Veronica Tsin Fong; Butzkueven, Helmut; Stankovich, Jim; O’Brien, Terence J.; Monif, Mastura

doi:10.1016/j.msard.2021.102962

Cited by 5 publications

(6 citation statements)

References 61 publications

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“…DCK expression is variable in different types of lymphocytes, dependent on their degree of activation. Cells of the immune system present different sensitivities to cladribine, depending on the expression levels of DCK and two cytosolic 5-nucleotidases (5-NT) isoforms most involved in adenosine metabolism: higher DCK to 5-NT ratio means higher cladribine sensitivity ( 60 ). Among lymphocytes, DCK:5-NT is very high for B cells, intermediate for CD4+ T cells, and low for CD8+ T cells ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cells of the immune system present different sensitivities to cladribine, depending on the expression levels of DCK and two cytosolic 5-nucleotidases (5-NT) isoforms most involved in adenosine metabolism: higher DCK to 5-NT ratio means higher cladribine sensitivity ( 60 ). Among lymphocytes, DCK:5-NT is very high for B cells, intermediate for CD4+ T cells, and low for CD8+ T cells ( 60 ). The CLARITY clinical trial revealed that oral cladribine treatment was associated with a profound decline in lymphocyte counts from baseline ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

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Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

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BackgroundMultiple sclerosis (MS) is an incurable autoimmune disease mediated by a heterogeneous T cell population (CD3+CD161+CXCR3−CCR6+IFNγ−IL17+, CD3+CXCR3+CCR6+IFNγ+IL17+, and CD3+CXCR3+IFNγ+IL17− phenotypes) that infiltrates the central nervous system, eliciting local inflammation, demyelination and neurodegeneration. Cladribine is a lymphocyte-depleting deoxyadenosine analogue recently introduced for MS therapy as a Disease Modifying Drug (DMD). Our aim was to establish a method for the early identification and prediction of cladribine responsiveness among MS patients.MethodsAn experimental model was designed to study the cytotoxic and immunomodulatory effect of cladribine. T cell subsets of naïve relapsing-remitting MS (RRMS) patients were analyzed ex vivo and in vitro comparatively to healthy controls (HC). Surviving cells were stimulated with rh-interleukin-2 for up to 14days. Cell proliferation and immunophenotype changes were analyzed after maximal (phorbol myristate acetate/ionomycin/monensin) and physiological T-cell receptor (CD3/CD28) activation, using multiparametric flow cytometry and xMAP technology.ResultsEx vivo CD161+Th17 cells were increased in RRMS patients. Ex vivo to in vitro phenotype shifts included: decreased CD3+CCR6+ and CD3+CD161+ in all subjects and increased CD3+CXCR3+ in RRMS patients only; Th17.1 showed increased proliferation vs Th17 in all subjects; CD3+IL17+ and CD3+IFNγ+IL17+ continued to proliferate till day 14, CD3+IFNγ+ only till day 7. Regarding cladribine exposure: RRMS CD3+ cells were more resistant compared to HC; treated CD3+ cells proliferated continuously for up to 14 days, while untreated cells only up to 7 days; both HC/RRMS CD3+CXCR3+ populations increased from baseline till day 14; in RRMS patients vs HC, IL17 secretion from cladribine-treated cells increased significantly, in line with the observed proliferation of CD3+IL17+ and CD3+IFNγ+IL17+ cells; in both HC/RRMS, cladribine led to a significant increase in CD3+IFNγ+ cells at day 7 only, having no further effect at day14. IFNγ and IL17 secreted in culture media decreased significantly from ex vivo to in vitro.ConclusionsCD3+ subtypes showed different responsiveness due to selectivity of cladribine action, in most patients leading to in vitro survival/proliferation of lymphocyte subsets known as pathogenic in MS. This in vitro experimental model is a promising tool for the prediction of individual responsiveness of MS patients to cladribine and other DMDs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

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“…Moreover, ratios of deoxycytidine kinase (DCK) and 5′-nucleotidase (5′-NT), which activate and inactivate CladT metabolites respectively, are presumed as the determinant of its cell type-specificity 3 , 4 . To our knowledge, DCK:5′-NT ratios have so far only been measured among NK cells 4 , 34 but not helper ILC. Strikingly, CD56bright and CD56dim NK cells show comparable DCK:5′-NT ratios 4 , 34 , but were affected differently by CladT in our study.…”

Section: Discussionmentioning

confidence: 99%

“…Among innate lymphoid cells (ILC), the effects of CladT have thus far only been investigated on NK cells, which rapidly declined from baseline and demonstrated a nadir at week 5 4 . However, the impacts of CladT on other ILC subsets have not been studied.…”

Section: Introductionmentioning

confidence: 99%

Mass cytometry reveals cladribine-induced resets among innate lymphoid cells in multiple sclerosis

Leitner

Juillard

et al. 2022

Sci Rep

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Here we present a comprehensive mass cytometry analysis of peripheral innate lymphoid cell (ILC) subsets in relapsing/remitting MS (RRMS) patients prior to and after onset of cladribine tablets (CladT). ILC analysis was conducted on CyTOF data from peripheral blood mononuclear cells (PBMC) of MS patients before, 2 and 6 months after onset of CladT, and non-MS controls. Dimensionality reduction was used for immunophenotyping ILC subsets. CladT reduced all ILC subsets, except for CD56bright NK cells and ILC2. Furthermore, CD38+ NK cell and CCR6+ ILC3 were excluded from CladT-induced immune cell reductions. Post-CladT replenishment by immature ILC was noted by increased CD5+ ILC1 proportions at 2 months, and boosted CD38−CD56bright NK cell numbers at 6 months. CladT induce immune cell depletion among ILC but exclude CD56bright NK cells and ILC2 subsets, as well as CD38+ NK cell and CCR6+ ILC3 immunophenotypes. Post-CladT ILC expansions indicate ILC reconstitution towards a more tolerant immune system phenotype.

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“…This activity is counterbalanced by 5-nucleotidase (5′NTase). Cladribine has well-defined and specifically designed activity against lymphocytes that leads to selective depletion and most importantly, cladribine only affects the adaptive immune system whilst sparing innate immune cells, thus reducing the risk of infections [ 4 , 13 , 21 , 22 ]. The high selectivity of cladribine for lymphocytes is due to the high ratio of DCK to 5′NTase and the high ratio of DCK to adenosine deaminase that leads to preferential accumulation in these cells.…”

Section: Cladribine Mechanism Of Action and Lymphocyte Selectivitymentioning

confidence: 99%

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

Giovannoni

Mathews

2022

Neurol Ther

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The development and impact of cladribine on lymphoid and myeloid cells in multiple sclerosis

Cited by 5 publications

References 61 publications

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Mass cytometry reveals cladribine-induced resets among innate lymphoid cells in multiple sclerosis

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

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