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 immunocompetent 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.


METHODS
Case-control study.


METHODS
Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.


METHODS
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.


METHODS
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.


CONCLUSIONS
Mitoxantrone may inhibit the migration of inflammatory cells into and within the central nervous system.
Kopadze
Tea
T
Department of Neurology, Research Group for Clinical and Experimental Neuroimmunology, Heinrich Heine University, Düsseldorf, Germany.
Dehmel
Thomas
T
Hartung
Hans-Peter
HP
Stüve
Olaf
O
Kieseier
Bernd C
BC
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000473:pathology*; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects*
D000970:Antineoplastic Agents; D002614:Chelating Agents; D004492:Edetic Acid; D008942:Mitoxantrone; D020782:Matrix Metalloproteinases