title: An aza-anthrapyrazole negatively regulates Th1 activity and suppresses experimental autoimmune encephalomyelitis.
abstract: Previously we showed that BBR3378, a novel analog of the anticancer drug mitoxantrone, had the ability to ameliorate ascending paralysis in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis, without the drug-induced cardiotoxicity or lymphopenia associated with mitoxantrone therapy. Chemotherapeutic drugs like mitoxantrone, a topoisomerase inhibitor, are thought to provide protection in inflammatory autoimmune diseases like EAE by inducing apoptosis in rapidly proliferating autoreactive lymphocytes. Here, we show that while BR3378 blocked cell division, T cells were still able to respond to antigenic stimulation and upregulate surface molecules indicative of activation. However, in contrast to mitoxantrone, BBR3378 inhibited the production of the proinflammatory cytokine IFN-γ both in recently activated T cell blasts and established Th1 effectors, while sparing the activities of IL-13-producing Th2 cells. IFN-γ is known to be regulated by the transcription factor T-bet. In addition to IFN-γ, in vitro and in vivo exposure to BBR3378 suppressed the expression of other T-bet regulated proteins, including CXCR3 and IL-2Rβ. Microarray analysis revealed BBR3378-induced suppression of additional T-bet regulated genes, suggesting that the drug might disrupt global Th1 programming. Importantly, BBR3378 antagonized ongoing Th1 autoimmune responses in vivo, modulated clinical disease and CNS inflammation in acute and relapsing forms of EAE. Therefore, BBR3378 may be a unique inhibitor of T-bet regulated genes and may have potential as a therapeutic intervention in human autoimmune disease.
authors.affiliation: The University of Toledo, Department of Biological Sciences, Toledo, OH, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Clark
authors.affiliation: The University of Toledo, Department of Biological Sciences, Toledo, OH, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Leaman
authors.affiliation: Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Hazelhurst
authors.affiliation: Ewha Woman's University, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Eun S
authors.initials: ES
authors.lastname: Hwang
authors.affiliation: The University of Toledo, Department of Biological Sciences, Toledo, OH, USA. Electronic address: anthony.quinn@utoledo.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Quinn
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D015551:Autoimmunity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008942:Mitoxantrone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D018943:Anthracyclines; C569470:BBR3378; D016207:Cytokines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C055925:anthrapyrazole; D008942:Mitoxantrone
keywords: Autoimmunity; Chemotherapy; EAE; IFN-γ; Multiple sclerosis; T cells; Th1