Therapeutic effect of PEGylated TNFR1-selective antagonistic mutant TNF in experimental autoimmune encephalomyelitis mice.
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.
Nomura
Tetsuya
T
Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation (NiBio), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Abe
Yasuhiro
Y
Kamada
Haruhiko
H
Shibata
Hiroko
H
Kayamuro
Hiroyuki
H
Inoue
Masaki
M
Kawara
Tomoyuki
T
Arita
Shuhei
S
Furuya
Takeshi
T
Yamashita
Takuya
T
Nagano
Kazuya
K
Yoshikawa
Tomoaki
T
Yoshioka
Yasuo
Y
Mukai
Yohei
Y
Nakagawa
Shinsaku
S
Taniai
Madoka
M
Ohta
Tsunetaka
T
Serada
Satoshi
S
Naka
Tetsuji
T
Tsunoda
Shin-ichi
S
Tsutsumi
Yasuo
Y
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*
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