Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats.
Pixantrone (BBR2778) (PIX) and mitoxantrone share the same mechanism of action because both drugs act as DNA intercalants and inhibitors of topoisomerase II. PIX is an interesting candidate immunosuppressant for the treatment of autoimmune diseases because of its reduced cardiotoxicity compared with mitoxantrone. The clinical response to conventional immunosuppressive treatments is poor in some patients affected by myasthenia gravis (MG), and new but well-tolerated drugs are needed for treatment-resistant MG. PIX was tested in vitro on rat T cell lines specific for the immunodominant peptide 97-116 derived from rat acetylcholine receptor (AChR), and showed strong antiproliferative activity in the nanomolar range. We demonstrate in this study that PIX administration reduced the severity of experimental autoimmune MG in Lewis rats. Biological and immunological analysis confirmed the effect of PIX, compared with vehicle-treated as well as mitoxantrone-treated experimental autoimmune MG rats. Anti-rat AChR Abs were significantly reduced in PIX-treated rats, and AChR content in muscles were found increased. Torpedo AChR-induced T cell proliferation tests were found reduced in both in vitro and ex vivo experiments. The effectiveness and the reduced cardiotoxicity make PIX a promising immunosuppressant agent suitable for clinical investigation in MG, although additional experiments are needed to confirm its safety profile in prolonged treatments.
Ubiali
Federica
F
Neurology IV, Neurological Institute Foundation Carlo Besta, Via Celoria 11, Milan, Italy.
Nava
Sara
S
Nessi
Valeria
V
Longhi
Renato
R
Pezzoni
Gabriella
G
Capobianco
Raffaella
R
Mantegazza
Renato
R
Antozzi
Carlo
C
Baggi
Fulvio
F
D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016056:Immunodominant Epitopes / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007546:Isoquinolines / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008969:Molecular Sequence Data; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D018733:Nicotinic Antagonists / Q000008:administration & dosage; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D011978:Receptors, Nicotinic / Q000378:metabolism; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014101:Torpedo
D016056:Immunodominant Epitopes; D007166:Immunosuppressive Agents; D007546:Isoquinolines; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C086548:pixantrone