TY - JOUR
T1 - Treatment of established relapsing experimental autoimmune encephalomyelitis with the proteasome inhibitor PS-519
AU - Vanderlugt, Carol L.
AU - Rahbe, Sandra M.
AU - Elliott, Peter J.
AU - Dal Canto, Mauro C.
AU - Miller, Stephen D.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - Experimental autoimmune encephalomyelitis
KW - Nuclear factor (NF)-κB
KW - Proteasome
KW - T lymphocytes
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U2 - 10.1006/jaut.2000.0370
DO - 10.1006/jaut.2000.0370
M3 - Article
C2 - 10756082
AN - SCOPUS:0033863764
VL - 14
SP - 205
EP - 211
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
IS - 3
ER -