Treatment of Established Relapsing Experimental Autoimmune Encephalomyelitis with the Proteasome Inhibitor PS-519¹

Authors: Vanderlugt C.L.¹; Rahbe S.M.¹; Elliott P.J.²; Dal Canto M.C.³; Miller S.D.¹

Source: Journal of Autoimmunity, Volume 14, Number 3, May 2000 , pp. 205-211(7)

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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)- kappa B 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- kappa B, 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- kappa B, may offer a novel and efficacious approach for the treatment of progressive autoimmune diseases, including MS. Copyright 2000 Academic Press

Language: English

Document Type: Research article

Affiliations: 1: Departments of Microbiology-Immunology, 38 Sidney Street, Cambridge, MA, 02139, U S A 2: ProScript, Inc., 38 Sidney Street, Cambridge, MA, 02139, U S A 3: Pathology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL, 60611, U S A

Publication date: 2000-05-01