title: Therapeutic effect of PEGylated TNFR1-selective antagonistic mutant TNF in experimental autoimmune encephalomyelitis mice.
abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease, the pathogenesis of which is related to elevated serum levels of tumor necrosis factor-α (TNF). Although anti-TNF therapy has been tested as a potential treatment for MS, no remission of symptoms was observed. Recent reports indicated that the TNFR1 signal was responsible for the pathogenesis of murine experimental autoimmune encephalomyelitis (EAE), while the TNFR2 signal was responsible for recovery of the pathogenesis of EAE. Therefore, selective blocking of TNFR1 appears to be a promising strategy for the treatment of MS. In this regard, we previously succeeded in developing a novel TNFR1-selective antagonistic TNF mutant (R1antTNF) by using phage display technology. Here, we have examined the therapeutic potential of R1antTNF using EAE mice. Treatment with PEGylated R1antTNF (PEG-R1antTNF) significantly improved the clinical score and cerebral demyelination at the onset of EAE. Considerable suppression of Th1 and Th17-type response was also observed in spleen and lymph node cells of mice given PEG-R1antTNF. Moreover, the administration of PEG-R1antTNF suppressed the infiltration of inflammatory cells containing Th1 and Th17 cells into the spinal cord. These results suggest that selective blocking of TNFR1 by PEG-R1antTNF could be an effective therapeutic strategy against MS.
authors.affiliation: Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation (NiBio), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nomura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Abe
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kamada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shibata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kayamuro
authors.forename: Masaki
authors.initials: M
authors.lastname: Inoue
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kawara
authors.forename: Shuhei
authors.initials: S
authors.lastname: Arita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Furuya
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kazuya
authors.initials: K
authors.lastname: Nagano
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mukai
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Madoka
authors.initials: M
authors.lastname: Taniai
authors.forename: Tsunetaka
authors.initials: T
authors.lastname: Ohta
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsutsumi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D009154:Mutation; D011092:Polyethylene Glycols / Q000737:chemistry*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D004337:Drug Carriers; D050505:Mutant Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols