Treatment of established relapsing experimental autoimmune encephalomyelitis with the proteasome inhibitor PS-519

Carol L. Vanderlugt, Sandra M. Rahbe, Peter J. Elliott, Mauro C. Dal Canto, Stephen D. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

PLP139-151-induced relapsing experimental autoimmune encephalomyelitis (R-EAE) in SJL mice is a Th1-mediated autoimmune demyelinating disease model for multiple sclerosis (MS) in which the primary disease relapse is mediated by T cells specific for the endogenous PLP178-191 epitope. This complex inflammatory process requires the co-ordinated expression of a wide variety of immune-related genes active at a variety of stages of the autoimmune process which are regulated, in part, by the transcription factor nuclear factor (NF)-κB which is activated via the ubiquitin-proteasome pathway. We asked if in vivo administration of a selective inhibitor of the ubiquitin-proteasome pathway, PS-519, which downregulates activation of NF-κB, could downregulate ongoing R-EAE. Administration of PS-519 during the remission phase, following acute clinical disease was effective in significantly reducing the incidence of clinical relapses, CNS histopathology, and T cell responses to both the initiating and relapse-associated PLP epitopes. The inhibition of clinical disease was dependent upon continuous administration of PS-519 in that recovery of T cell function and onset of disease relapses developed within 10-14 days of drug withdrawal. The data suggest that targeting the ubiquitin proteasome pathway, in particular NF-κB, may offer a novel and efficacious approach for the treatment of progressive autoimmune diseases, including MS. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)205-211
Number of pages7
JournalJournal of Autoimmunity
Volume14
Issue number3
DOIs
StatePublished - 2000

Keywords

  • Autoimmunity
  • Experimental autoimmune encephalomyelitis
  • Nuclear factor (NF)-κB
  • Proteasome
  • T lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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