Sistema de Salut de Catalunya
Institut Català de la Salut
[Fissolo N, Calvo-Barreiro L, Eixarch H, Espejo C, Montalban X, Comabella M] Centre d’Esclerosi Múltiple de Catalunya (CEMCAT), Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Boschert U] Ares Trading, SA, 1262 Eysins, Switzerland. Merck KGaA, 64297 Darmstadt, Germany
Vall d'Hebron Barcelona Hospital Campus
2022-06-15T11:52:04Z
2022-06-15T11:52:04Z
2021-12
Cladribine; Flow-cytometry; Multiple sclerosis
Cladribina; Citometría de flujo; Esclerosis múltiple
Cladribina; Citometria de flux; Esclerosi múltiple
Cladribine is a synthetic deoxyadenosine analogue with demonstrated efficacy in patients with relapsing-remitting multiple sclerosis (MS). The main mechanism of action described for cladribine is the induction of a cytotoxic effect on lymphocytes, leading to a long-term depletion of peripheral T and B cells. Besides lymphocyte toxicity, the mode of action may include immunomodulatory mechanisms affecting other cells of the immune system. In order to induce its beneficial effects, cladribine is phosphorylated inside the cell by deoxycytidine kinase (DCK) to its active form. However, the mechanism of action of cladribine may also include immunomodulatory pathways independent of DCK activation. This in vitro study was designed to explore the impact of cladribine on peripheral blood mononuclear cells (PBMC) subsets, and to assess whether the immunomodulatory mechanisms induced by cladribine depend on the activation of the molecule. To this end, we obtained PBMCs from healthy donors and MS patients and performed proliferation, apoptosis and activation assays with clinically relevant concentrations of cladribine in DCK-dependent and -independent conditions. We also evaluated the effect of cladribine on myeloid lineage-derived cells, monocytes and dendritic cells (DCs). Cladribine decreased proliferation and increased apoptosis of lymphocyte subsets after prodrug activation via DCK. In contrast, cladribine induced a decrease in immune cell activation through both DCK-dependent and -independent pathways (not requiring prodrug activation). Regarding monocytes and DCs, cladribine induced cytotoxicity and impaired the activation of classical monocytes, but had no effect on DC maturation. Taken together, these data indicate that cladribine, in addition to its cytotoxic function, can mediate immunomodulation in different immune cell populations, by regulating their proliferation, maturation and activation.
This work was supported by Merck. This study was sponsored by Merck (CrossRef Funder ID: 10.13039/100009945).
Article
Published version
English
Esclerosi múltiple - Tractament; Resposta immunitària - Regulació; Cèl·lules - Proliferació; DISEASES::Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis::Multiple Sclerosis, Relapsing-Remitting; Other subheadings::Other subheadings::Other subheadings::/drug therapy; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Biological Therapy::Immunomodulation; PHENOMENA AND PROCESSES::Cell Physiological Phenomena::Cell Growth Processes::Cell Proliferation; ENFERMEDADES::enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple::esclerosis múltiple recurrente-remitente; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapia biológica::inmunomodulación; FENÓMENOS Y PROCESOS::fenómenos fisiológicos celulares::procesos de crecimiento celular::proliferación celular
MDPI
Cells;10(12)
https://doi.org/10.3390/cells10123488
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Articles científics - HVH [3439]
Articles científics - VHIR [1665]
