Inhibition by mitoxantrone of in vitro migration of immunocompetent cells -: A possible mechanism for therapeutic efficacy in the treatment of multiple sclerosis

Background: Damage of the blood-brain barrier and invasion of immocompetent cells into the central nervous system represent key events in the immunopathogenesis of multiple sclerosis. Mitoxantrone hydrochloride reduces progression of disability and clinical exacerbations in patients with multiple sclerosis. Its precise mode of action is unclear. Objective: To investigate the effects of mitoxantrone on the migratory capacity of immunocompetent cells ex vivo and in vitro. Design: Case-control study. Setting: Department of Neurology, Heinrich Heine University, Dusseldorf, Germany. Participants: Peripheral blood mononuclear cells (PBMCs) were obtained from 11 patients with multiple sclerosis before and after intravenous mitoxantrone treatment; PBMCs from 5 healthy control donors were treated with mitoxantrone in vitro. Main Outcome Measures: The migratory capacity was studied in an in vitro Boyden chamber assay; cells and their rates of migration were analyzed by light microscopy and flow cytometry. To determine the specificity of our findings, PBMCs were treated with perfosfamide in vitro. Results: Mitoxantrone decreased the migratory capacity of CD14(+) monocytes; and (to a lesser degree) of CD4(+) and CD8(+) T lymphocytes. These observations were confirmed when control PBMCs were treated with an equivalent dose of mitoxantrone in vitro. Similar effects were seen when PBMCs were preincubated with perfosfamide. The inhibitory effects of mitoxantrone on the migratory capacity of PBMCs were mediated by reduced matrix metalloproteinase 9 activity, as demonstrated by zymography, polymerase chain reaction, and inhibitory studies. Conclusion: Mitoxantrone may inhibit the migration of inflammatory cells into and within the central nervous system.