Protection against experimental autoimmune encephalomyelitis by a proteasome modulator.
The capacity of interferon beta to alter the course of multiple sclerosis has promoted a new therapeutic concept, based upon the modulation of the immune response rather than its suppression. As the proteasome plays a crucial role in the control of the inflammatory process and immune cell survival, targeting the proteasome appears as a novel approach for the prevention and treatment of inflammatory autoimmune diseases. We have previously shown that ritonavir, an HIV-1 protease inhibitor used in AIDS therapy, can modulate the proteasome function by inhibiting the chymotrypsin-like activity and enhancing the trypsin-like activity. We have, therefore, explored its therapeutic potential on experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis, in Lewis rats and SJL mice. Daily administration of ritonavir during autoimmune antigen stimulation prevented clinical symptoms of EAE in a dose- and time-dependent manner. This protection was accompanied by an inhibition of the mononuclear cell infiltration into the central nervous system usually observed in EAE. Despite a complete absence of clinical symptoms during first EAE induction, ritonavir-treated animals became resistant to further induction of EAE, suggesting an immune mechanism of protection. These results suggest that proteasome modulation using ritonavir or analogues may be of interest for patients with multiple sclerosis.
Hosseini
H
H
INSERM U421, Faculté de Médecine 8, rue du général Sarrail, 94010 cedex, Créteil, France.
André
P
P
Lefevre
N
N
Viala
L
L
Walzer
T
T
Peschanski
M
M
Lotteau
V
V
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000187:drug effects*; D004676:Myelin Basic Protein; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011917:Rats, Inbred Lew; D019438:Ritonavir / Q000494:pharmacology*; D019258:Saquinavir / Q000494:pharmacology*; D013116:Spinal Cord / Q000473:pathology
D017320:HIV Protease Inhibitors; D009097:Multienzyme Complexes; D004676:Myelin Basic Protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D019258:Saquinavir; D019438:Ritonavir