Immunomodulatory Effects Associated with Cladribine Treatment
Fissolo, Nicolás (Hospital Universitari Vall d'Hebron)
Calvo-Barreiro, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Eixarch, Herena (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Boschert, Ursula (Merck KGaA, 64297 Darmstadt, Germany)
Espejo, Carmen (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Montalban, Xavier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Comabella, Manuel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona. Departament de Medicina

Fecha:	2021
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Multiple sclerosis ; Cladribine ; Immune-regulation ; Flow-cytometry
Publicado en:	Cells, Vol. 10 (december 2021) , art. 3488, ISSN 2073-4409

DOI: 10.3390/cells10123488
PMID: 34943995

13 p, 1.5 MB

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