title: Mitoxantrone induces natural killer cell maturation in patients with secondary progressive multiple sclerosis.
abstract: Mitoxantrone is one of the few drugs approved for the treatment of progressive multiple sclerosis (MS). However, the prolonged use of this potent immunosuppressive agent is limited by the appearance of severe side effects. Apart from its general cytotoxic effect, the mode of action of mitoxantrone on the immune system is poorly understood. Thus, to develop safe therapeutic approaches for patients with progressive MS, it is essential to elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated a prospective single-arm open-label study with 19 secondary progressive MS patients. We investigated long-term effects of mitoxantrone on patient peripheral immune subsets using flow cytometry. While we corroborate that mitoxantrone persistently suppresses B cells in vivo, we show for the first time that treatment led to an enrichment of neutrophils and immunomodulatory CD8(low) T cells. Moreover, sustained mitoxantrone applications promoted not only persistent NK cell enrichment but also NK cell maturation. Importantly, this mitoxantrone-induced NK cell maturation was seen only in patients that showed a clinical response to treatment. Our data emphasize the complex immunomodulatory role of mitoxantrone, which may account for its benefit in MS. In particular, these results highlight the contribution of NK cells to mitoxantrone efficacy in progressive MS.
authors: Experimental and Clinical Research Center, Charité Medical Faculty, Berlin, Germany.
authors: Coralie
authors: C
authors: Chanvillard
authors: Jason M
authors: JM
authors: Millward
authors: Marta
authors: M
authors: Lozano
authors: Isabell
authors: I
authors: Hamann
authors: Friedemann
authors: F
authors: Paul
authors: Frauke
authors: F
authors: Zipp
authors: Jan
authors: J
authors: Dörr
authors: Carmen
authors: C
authors: Infante-Duarte
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000494:pharmacology* / Q000627:therapeutic use*; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D009504:Neutrophils / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008942:Mitoxantrone