Protection against experimental autoimmune encephalomyelitis by a proteasome modulator

The capacity of interferon beta to alter the course of multiple sclerosis h as promoted a new therapeutic concept, based upon the modulation of the imm une 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 th at ritonavir, an HIV-1 protease inhibitor used in AIDS therapy, can modulat e the proteasome function by inhibiting the chymotrypsin-like activity and enhancing the trypsin-like activity. We have, therefore, explored its thera peutic potential on experimental autoimmune encephalomyelitis (EAE), an exp erimental model of multiple sclerosis, in Lewis rats and SJL mice. Daily ad ministration of ritonavir during autoimmune antigen stimulation prevented c linical symptoms of EAE in a dose-and time-dependent manner. This protectio n was accompanied by an inhibition of the mononuclear cell infiltration int o the central nervous system usually observed in EAE. Despite a complete ab sence of clinical symptoms during first EAE induction, ritonavir-treated an imals became resistant to further induction of EAE, suggesting an immune me chanism of protection. These results suggest that proteasome modulation usi ng ritonavir or analogues may be of interest for patients with multiple scl erosis. (C) 2001 Elsevier Science BN, All rights reserved.