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

• Published in: Journal of autoimmunity 2000-05, Vol.14 (3), p.205-211
• Main Authors: VANDERLUGT, C. L, RAHBE, S. M, ELLIOTT, P. J, DAL CANTO, M. C, MILLER, S. D
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cysteine Endopeptidases - immunology; Cysteine Proteinase Inhibitors - immunology; Cysteine Proteinase Inhibitors - therapeutic use; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Epitopes, T-Lymphocyte - immunology; Experimental and animal immunopathology. Animal models; Female; Immunopathology; Medical sciences; Mice; Multienzyme Complexes - immunology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Myelin Proteolipid Protein - immunology; Neurology; Peptide Fragments - immunology; Proteasome Endopeptidase Complex; proteasome inhibitor PS-519; Recurrence; Spinal Cord - immunology; T-Lymphocytes - immunology
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1006/jaut.2000.0370

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.