Cladribine impedes<i>in vitro</i>migration of mononuclear cells: a possible implication for treating multiple sclerosis

Kopadze, Tea; Döbert, M.; Leussink, Verena I.; Dehmel, Thomas; Kieseier, Bernd C.

doi:10.1111/j.1468-1331.2008.02433.x

Cited by 45 publications

(33 citation statements)

References 14 publications

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“…For cladribine several studies demonstrated reductions in the release of pro- and anti-inflammatory cytokines, chemokines, and adhesion molecules, as well as a decrease in the cellular migratory capacity of treated cells [19–21]. However, these experiments were performed in the presence of cladribine; therefore, toxic effects rather than modulation of cell function could account for the observed changes.…”

Section: Introductionmentioning

confidence: 99%

Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells

Korsen

Alonso²,

Peix

et al. 2015

PLoS ONE

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Background and ObjectivesCladribine is a cytotoxic drug which ameliorates the clinical course of relapsing-remitting multiple sclerosis. In addition to cytotoxicity, the mode of action may include immunomodulatory mechanisms. This in vitro study was designed to investigate cladribine’s effects on cell function after the removal of cladribine to distinguish cytotoxic versus immunomodulatory effects.MethodsCells were incubated in the absence or presence of cladribine (1×10-8 M to 1×10-5 M) for 72 h. Cladribine was removed from the cell culture and surviving peripheral blood mononuclear cells were cultured up to 58 days to determine the immunomodulatory effects of cladribine on cell function (e.g., proliferation and cytokine release).ResultsIn the long-term, brief cladribine exposure did not impair the proliferation of surviving peripheral blood mononuclear cells. However, it induced an anti-inflammatory shift in the cytokine milieu with significantly enhanced release of IL-4 (Days 9 and 44, p<0.01; Day 58, p<0.05) and IL-5 (Day 9, p<0.01), resulting in an increased IL-4/INF-gamma ratio (Days 9 and 44, p<0.01; Day 58, p<0.05). Additionally, a trend towards an increased IL-10 production was observed. No changes were found in the production of IFN-gamma, TNF-alpha, IL-6, IL-8, IL-17A, IL-23 or NGF-beta.Conclusions In vitro cladribine exposure induces a sustained anti-inflammatory shift in the cytokine profile of surviving peripheral blood mononuclear cells. This immunomodulatory action might contribute to cladribine’s beneficial effects in the treatment of multiple sclerosis.

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Section: Introductionmentioning

confidence: 99%

Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells

Korsen

Alonso²,

Peix

et al. 2015

PLoS ONE

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“…T cells and also impacts on B cells, but has only minor effects on natural killer (NK) cells [36,40]. Recent evidence indicates that cladribine may also impede the influx of T cells into the CNS [41]. The sustained effects of cladribine treatment support the use of an annual, short-course dosing regimen.…”

Section: Mechanism Of Action Of Cladribinementioning

confidence: 98%

Development of oral cladribine for the treatment of multiple sclerosis

et al. 2009

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Multiple sclerosis (MS) is a chronic immune-mediated disorder of the CNS in which autoreactive CD4+ and CD8+ T lymphocytes, B lymphocytes, antibodies, macrophages and cytokines synergize to attack myelin sheaths and injure underlying axons. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Of all the potential new oral MS agents in development, cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers targeted, sustained regulation of the immune system and that has a well-characterized safety profile, derived from more than 15 years of use of the parenteral formulation in oncology indications and MS. This paper discusses the need for new MS therapies to improve treatment adherence, and reviews the mechanism of action, existing efficacy and safety data, and the clinical development of oral cladribine. The need for continuous risk monitoring for all new potent immunoactive drugs under development is emphasized. Preliminary results of the 96-week, double-blind, randomized, placebo-controlled, multicenter CLARITY (CLAdRIbine Tablets Treating MS OrallY) study are encouraging and provide the first complete phase III data on an oral DMD for MS.

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“…The same study showed that mean natural killer (NK) cell counts dropped during the first months of cladribine treatment, but recovered after 7 months 29. Cladribine may also impair cellular migration into the CNS 30. Using an in vitro Boyden chamber and fibronectin layer, Kopadze et al, studied the effect of cladribine on the migratory capacity of immunocompetent cells in both MS patients as well as controls.…”

Section: Mechanism Of Action Metabolism and Pharmacokinetic Profilementioning

confidence: 99%

Current and Emerging Therapies for the Treatment of Multiple Sclerosis: Focus on Cladribine

Schreiner

Miravalle

2012

J Cent Nerv Syst Dis

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Multiple Sclerosis (MS) is a chronic inflammatory, immune-mediated, demyelinating disorder of the central nervous system with a heterogeneous clinical presentation and pathology in which activated lymphocytes play an important role in mediating tissue damage. Until recently, all first line therapies for MS were injectable. Several oral medications have been studied for preventative treatment of MS. Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog that has been used for the treatment of several hematologic neoplasms, with a unique lymphcytotoxic mechanism of action. Cladribine has been investigated as treatment of MS for more than 15 years. A recent placebo-controlled, double-blind study of cladribine, CLARITY, showed decreased relapse rates, risk of disability progression and MRI measures of disease activity at 96 weeks. Cladribine’s strengths included high efficacy and convenient, biannual oral dosing. However, concerns about safety prevented the FDA from approving cladribine in 2011. Thus, use of cladribine for treatment of relapsing and remitting multiple sclerosis will remain off-label.

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Cladribine impedesin vitromigration of mononuclear cells: a possible implication for treating multiple sclerosis

Abstract: Cladribine might achieve, at least in part, its clinical and paraclinical efficacy by inhibiting the migration of inflammatory cells into and within the CNS.

Cited by 45 publications

References 14 publications

Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells

Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells

Development of oral cladribine for the treatment of multiple sclerosis

Current and Emerging Therapies for the Treatment of Multiple Sclerosis: Focus on Cladribine

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