| First Author | Vanderlugt CL | Year | 2000 |
| Journal | J Autoimmun | Volume | 14 |
| Issue | 3 | Pages | 205-11 |
| PubMed ID | 10756082 | Mgi Jnum | J:61811 |
| Mgi Id | MGI:1355613 | Doi | 10.1006/jaut.2000.0370 |
| Citation | Vanderlugt CL, et al. (2000) Treatment of established relapsing experimental autoimmune encephalomyelitis with the proteasome inhibitor PS-519. J Autoimmun 14(3):205-11 |
| abstractText | 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)-kappaB 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-kappaB, 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-kappaB, may offer a novel and efficacious approach for the treatment of progressive autoimmune diseases, including MS. Copyright 2000 Academic Press. |
