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: Tetsuya Nomura, Yasuhiro Abe, Haruhiko Kamada, Hiroko Shibata, Hiroyuki Kayamuro, Masaki Inoue, Tomoyuki Kawara, Shuhei Arita, Takeshi Furuya, Takuya Yamashita, Kazuya Nagano, Tomoaki Yoshikawa, Yasuo Yoshioka, Yohei Mukai, Shinsaku Nakagawa, Madoka Taniai, Tsunetaka Ohta, Satoshi Serada, Tetsuji Naka, Shin-ichi Tsunoda, Yasuo Tsutsumi
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 149 Issue 1 Pg. 8-14 (Jan 05 2011) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 20036293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2009 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Drug Carriers
• Mutant Proteins
• Receptors, Tumor Necrosis Factor, Type I
• Tnfrsf1a protein, mouse
• Tumor Necrosis Factor-alpha
• Polyethylene Glycols

Topics

• Animals
• Cell Proliferation (drug effects)
• Cytokines (blood, immunology)
• Drug Carriers (chemistry)
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, pathology)
• Lymph Nodes (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Mutant Proteins (administration & dosage, genetics, therapeutic use)
• Mutation
• Polyethylene Glycols (chemistry)
• Receptors, Tumor Necrosis Factor, Type I (antagonists & inhibitors)
• Spinal Cord (drug effects, immunology, pathology)
• Spleen (drug effects, immunology)
• T-Lymphocytes (drug effects, immunology)
• Tumor Necrosis Factor-alpha (administration & dosage, genetics, therapeutic use)