Treatment of established relapsing experimental autoimmune encephalomyelitis with the proteasome inhibitor PS-5191

CL Vanderlugt, SM Rahbe, PJ Elliott… - Journal of …, 2000 - Elsevier
CL Vanderlugt, SM Rahbe, PJ Elliott, MC Dal Canto, SD Miller
Journal of autoimmunity, 2000Elsevier
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 …
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.
Elsevier