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

J Immunol. 2008 Jun 15;180(12):7989-8003. doi: 10.4049/jimmunol.180.12.7989.


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.

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Arthritis, Experimental / enzymology
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / prevention & control*
  • Azepines / administration & dosage*
  • Azepines / therapeutic use
  • Benzofurans / administration & dosage*
  • Benzofurans / therapeutic use
  • Cathepsins / antagonists & inhibitors*
  • Cattle
  • Cell Line, Tumor
  • Cells, Cultured
  • Collagen Type II / immunology*
  • Cysteine Proteinase Inhibitors / administration & dosage
  • Cysteine Proteinase Inhibitors / therapeutic use
  • Encephalomyelitis, Autoimmune, Experimental / enzymology
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Leucine / administration & dosage
  • Leucine / analogs & derivatives*
  • Leucine / therapeutic use
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Protein Processing, Post-Translational / drug effects*
  • Protein Processing, Post-Translational / immunology
  • Pyridines / administration & dosage*
  • Pyridines / therapeutic use
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / enzymology


  • 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
  • Antigens, Differentiation, B-Lymphocyte
  • Azepines
  • Benzofurans
  • Collagen Type II
  • Cysteine Proteinase Inhibitors
  • Histocompatibility Antigens Class II
  • Pyridines
  • SB 331750
  • invariant chain
  • Cathepsins
  • Leucine