Multiple sclerosis: Mitoxantrone promotes differential effects on immunocompetent cells in vitro.
Mitoxantrone is an anti-neoplastic anthracenedione derivative that, based on its immunosuppressive properties, is approved for the treatment of severe forms of relapsing-remitting or secondary progressive multiple sclerosis (MS). Whether the beneficial clinical effects of mitoxantrone in MS are due to a broad immunosuppression, or whether there is a specific mechanism of action remains unknown. Peripheral blood mononuclear cells (PBMCs) from untreated or interferon-beta-treated patients with MS or from healthy donors were stimulated in the presence or absence of mitoxantrone. Irrespective of the source of the cells and the cellular phenotype, mitoxantrone inhibited proliferation of activated PBMCs, B lymphocytes, or antigen-specific T-cell lines (TCLs) stimulated on antigen-presenting cells (APCs) in a dose-dependent manner. For functional analysis, TCLs or APCs were incubated separately with mitoxantrone. Pre-incubation of APC more effectively impaired TCL proliferation than pre-incubation of TCLs. Production of cytokines, expression of activation markers, matrix metalloproteinases, and chemokine receptors were not influenced substantially by mitoxantrone. In contrast, in dendritic cells (DCs), mitoxantrone interfered with the antigen-presenting capabilities. For evaluation of apoptotic cell death of target cells, annexin-V-conjugates and a DNA fragmentation assay were applied. Mitoxantrone induced apoptosis of PBMCs, monocytes and DCs at low concentrations, whereas higher doses caused cell lysis. Our observations suggest that the beneficial effects of mitoxantrone in MS result (i) from its immunosuppressive action based on nonspecific cytotoxic effects on lymphocytes, (ii) by inducing programmed cell death of professional APCs, such as DCs.
Neuhaus
Oliver
O
Department of Neurology, Heinrich-Heine-Universität, Moorenstr. 5, 40225 Düsseldorf, Germany. oliver.neuhaus@uni-duesseldorf.de
Wiendl
Heinz
H
Kieseier
Bernd C
BC
Archelos
Juan J
JJ
Hemmer
Bernhard
B
Stüve
Olaf
O
Hartung
Hans-Peter
HP
D000328:Adult; D017304:Annexin A5; D001773:Blood Cells / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000473:pathology*; D009498:Neurotoxins / Q000494:pharmacology; D011419:Propidium; D013601:T-Lymphocytes / Q000187:drug effects; D013744:Tetanus Toxin / Q000494:pharmacology; D013936:Thymidine / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
D017304:Annexin A5; D016207:Cytokines; D007166:Immunosuppressive Agents; D009498:Neurotoxins; D013744:Tetanus Toxin; D014316:Tritium; D011419:Propidium; D008942:Mitoxantrone; D020782:Matrix Metalloproteinases; D013936:Thymidine