Inhibition of invariant chain processing, antigen-induced proliferative responses, and the development of collagen-induced arthritis and experimental autoimmune encephalomyelitis by a small molecule cysteine protease inhibitor.
Members of the papain family of cysteine proteases (cathepsins) mediate late stage processing of MHC class II-bound invariant chain (Ii), enabling dissociation of Ii, and binding of antigenic peptide to class II molecules. Recognition of cell surface class II/Ag complexes by CD4(+) T cells then leads to T cell activation. Herein, we demonstrate that a pan-active cathepsin inhibitor, SB-331750, attenuated the processing of whole cell Ii p10 to CLIP by Raji cells, and DBA/1, SJL/J, and C57BL/6 splenocytes. In Raji cells and C57BL/6 splenocytes, SB-331750 inhibited class II-associated Ii processing and reduced surface class II/CLIP expression, whereas in SB-331750-treated DBA/1 and SJL/J splenocytes, class II-associated Ii processing intermediates were undetectable. Incubation of lymph node cells/splenocytes from collagen-primed DBA/1 mice and myelin basic protein-primed SJL/J mice with Ag in the presence of SB-331750 resulted in concentration-dependent inhibition of Ag-induced proliferation. In vivo administration of SB-331750 to DBA/1, SJL/J, and C57BL/6 mice inhibited splenocyte processing of whole cell Ii p10 to CLIP. Prophylactic administration of SB-331750 to collagen-immunized/boosted DBA/1 mice delayed the onset and reduced the severity of collagen-induced arthritis (CIA), and reduced paw tissue levels of IL-1beta and TNF-alpha. Similarly, treatment of myelin basic protein-primed SJL/J lymph node cells with SB-331750 delayed the onset and reduced the severity of adoptively transferred experimental autoimmune encephalomyelitis (EAE). Therapeutic administration of SB-331750 reduced the severity of mild/moderate CIA and EAE. These results indicate that pharmacological inhibition of cathepsins attenuates CIA and EAE, potentially via inhibition of Ii processing, and subsequent Ag-induced T cell activation.
Respiratory and Inflammation Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA. patty_podolin@gsk.com
Patricia L
PL
Podolin
Brian J
BJ
Bolognese
Donald C
DC
Carpenter
T Gregg
TG
Davis
Roy A
RA
Johanson
Josephine H
JH
Fox
Edward
E
Long
Xiaoyang
X
Dong
Robert W
RW
Marquis
Stephen M
SM
Locastro
Gerald J
GJ
Terfloth
Edit
E
Kurali
John J
JJ
Peterson
Brian R
BR
Smith
Michael S
MS
McQueney
Dennis S
DS
Yamashita
Elizabeth A
EA
Capper-Spudich
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D001381:Azepines / Q000008:administration & dosage* / Q000627:therapeutic use; D001572:Benzofurans / Q000008:administration & dosage* / Q000627:therapeutic use; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002417:Cattle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000276:immunology; D011725:Pyridines / Q000008:administration & dosage* / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
C425781:5-(2-morpholin-4-ylethoxy)benzofuran-2-carboxylic acid (3-methyl-1-(3-oxo-1-(2-(3-pyridin-2-ylphenyl)acetyl)azepan-4-ylcarbamoyl)butyl)amide; D000944:Antigens, Differentiation, B-Lymphocyte; D001381:Azepines; D001572:Benzofurans; D024043:Collagen Type II; D015853:Cysteine Proteinase Inhibitors; D000949:Histocompatibility Antigens Class II; D011725:Pyridines; C467690:SB 331750; C045084:invariant chain; D002403:Cathepsins; D007930:Leucine