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

PLP139-151-induced relapsing experimental autoimmune encephalomyelitis (R-E AE) in SJL mice is a Th1-mediated autoimmune demyelinating disease model fo r multiple sclerosis (MS) in which the primary disease relapse is mediated by T cells specific for the endogenous PLP178-191 epitope. This complex inf lammatory process requires the co-ordinated expression of a wide variety of immune-related genes active at a variety of stages of the autoimmune proce ss which are regulated, in part, by the transcription factor nuclear factor (NF)-kappa B which is activated via the ubiquitin-proteasome pathway. We a sked if in vivo administration of a selective inhibitor of the ubiquitin-pr oteasome pathway, PS-519, which downregulates activation of NF-kappa B, cou ld downregulate ongoing R-EAE. Administration of PS-519 during the remissio n phase, following acute clinical disease was effective in significantly re ducing the incidence of clinical relapses, CNS histopathology, and T cell r esponses to both the initiating and relapse-associated PLP epitopes. The in hibition of clinical disease was dependent upon continuous administration o f 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 targe ting the ubiquitin proteasome pathway, in particular NF-kappa B, may offer a novel and efficacious approach for the treatment of progressive autoimmun e diseases, including MS. (C) 2000 Academic Press.