title: Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity.
abstract: The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice after oral administration. Functional activity of the compound was shown by a reduction in the OVA-specific response of OVA-sensitized splenocytes from C57Bl/6 mice as well as from OVA-TCR transgenic mice (DO11.10). Since these studies revealed a selective suppression of the Th1 and Th17 cytokines causing a shift to Th2, CSI-75 was tested in the murine HC-gp39-immunization model. Indeed, CSI-75 specifically reduced the circulating HC-gp39-specific IgG2a in these mice indicating selective inhibition of the Th1 type of response in vivo. The importance of especially the Th1 and Th17 cell subsets in the pathology of autoimmune diseases, renders CatS inhibition a highly interesting potential therapeutic treatment of autoimmune diseases. Therefore, CSI-75 was tested in a murine model of multiple sclerosis (i.e. experimental autoimmune encephalomyelitis (EAE)) in a semi-therapeutic setting (ie. oral treatment after initial sensitization to antigen). Finally, in a murine model with features resembling rheumatoid arthritis (the collagen-induced arthritis (CIA) model), CSI-75 was tested in a therapeutic manner (after disease development). CSI-75 caused a significant reduction in disease score in both disease models, indicating a promising role for CatS inhibitors in the area of therapeutic treatments for autoimmune diseases.
authors: MSD, Newhouse Industrial Estate, Newhouse, Motherwell ML15SH, UK. mdlbaugh@hotmail.com
authors: Mark
authors: M
authors: Baugh
authors: Darcey
authors: D
authors: Black
authors: Paul
authors: P
authors: Westwood
authors: Emma
authors: E
authors: Kinghorn
authors: Kieran
authors: K
authors: McGregor
authors: John
authors: J
authors: Bruin
authors: William
authors: W
authors: Hamilton
authors: Maureen
authors: M
authors: Dempster
authors: Christopher
authors: C
authors: Claxton
authors: Jiaqiang
authors: J
authors: Cai
authors: Jonathan
authors: J
authors: Bennett
authors: Clive
authors: C
authors: Long
authors: Heather
authors: H
authors: McKinnon
authors: Paul
authors: P
authors: Vink
authors: Leontien
authors: L
authors: den Hoed
authors: Monika
authors: M
authors: Gorecka
authors: Kalpit
authors: K
authors: Vora
authors: Ethan
authors: E
authors: Grant
authors: M David
authors: MD
authors: Percival
authors: A Mieke H
authors: AM
authors: Boots
authors: Marie-José
authors: MJ
authors: van Lierop
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D018417:Th1 Cells / Q000502:physiology
chemical_list: C559848:CSI-75; D010880:Piperidines; D011480:Protease Inhibitors; D011725:Pyridines; D002403:Cathepsins; C028217:cathepsin S