Treatment of established relapsing experimental autoimmune encephalomyelitis with the proteasome inhibitor PS-519.
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.
Vanderlugt
C L
CL
Departments of Microbiology-Immunology, 38 Sidney Street, Cambridge, MA 02139, USA.
Rahbe
S M
SM
Elliott
P J
PJ
Dal Canto
M C
MC
Miller
S D
SD
D000818:Animals; D003546:Cysteine Endopeptidases / Q000276:immunology*; D015853:Cysteine Proteinase Inhibitors / Q000276:immunology* / Q000627:therapeutic use; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D051379:Mice; D009097:Multienzyme Complexes / Q000276:immunology*; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D012008:Recurrence; D013116:Spinal Cord / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D015853:Cysteine Proteinase Inhibitors; D018984:Epitopes, T-Lymphocyte; D009097:Multienzyme Complexes; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); C094242:myelin proteolipid protein (178-191); D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex