Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes.
Treosulfan (dihydroxybusulfane, DHB, L-threitol-1,4-bis [methane sulfonate]) is a cytostatic alkylating agent with a favorable profile of side effects. Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) induced in DA (RT1(av1)) rats resembles multiple sclerosis (MS) in many aspects since central nervous system (CNS) pathology shows inflammation, demyelination and axonal loss. Moreover, DA rats develop a chronic disease course. We here explored the efficacy of treosulfan in the treatment of MOG-induced EAE in DA rats. A single dose of treosulfan (1 g/kg body weight i.p.) at the day of immunization significantly reduced disease severity compared with PBS-treated controls. In addition, after disease had evolved, a single dose of treosulfan (1 g/kg body weight) given i.p. on day 14 post-immunization (p.i.) improved long-term disease outcome. Treatment with treosulfan resulted in reduced mRNA expression of IL-12 and interferon (IFN)-gamma in draining lymph nodes and reduced numbers of IFN-gamma-secreting MOG-specific T cells. No myelosuppression was observed. Treosulfan was applied to different subsets of cultured human blood mononuclear cells in order to asses the effects on human immune cells in vitro: Treosulfan reduced proliferative capacity and increased apoptosis in T cells and antigen-presenting cells. In light of the beneficial effects in EAE in vivo and the in vitro immunosuppressive and pro-apoptotic capacities in cultured human mononuclear immune effector cells, these data may support a potential role of treosulfan, an agent with high immunosuppressive capacity and low toxicity, in the treatment of MS.
Experimental Neuroimmunology Laboratory, Department of General Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany. robert.weissert@uni-tuebingen.de
Robert
R
Weissert
Heinz
H
Wiendl
Heike
H
Pfrommer
Maria K
MK
Storch
Bettina
B
Schreiner
Silvia
S
Barth
Thomas
T
Seifert
Arthur
A
Melms
Johannes
J
Dichgans
Michael
M
Weller
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000187:drug effects; D002066:Busulfan / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use* / Q000633:toxicity; D007271:Injections, Intradermal; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D007166:Immunosuppressive Agents; C571326:MOG protein, human; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; C018404:treosulfan; D002066:Busulfan