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 language | English (US) |
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Pages (from-to) | 205-211 |
Number of pages | 7 |
Journal | Journal of Autoimmunity |
Volume | 14 |
Issue number | 3 |
DOIs | |
State | Published - 2000 |
Funding
This work was supported in part by a grant from ProScript, Inc., USPHS NIH Grants NS/AI-34819, NS-26543, NS-30871 and NS-13011 and National Multiple Sclerosis Society Grants RG2775 and RG2893.
Keywords
- Autoimmunity
- Experimental autoimmune encephalomyelitis
- Nuclear factor (NF)-κB
- Proteasome
- T lymphocytes
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology