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Ann Rheum Dis. 2015 Feb;74(2):452-63. doi: 10.1136/annrheumdis-2013-203717. Epub 2013 Dec 3.

Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming.

Author information

1
Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany.
2
CV & Metabolism DTA, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.

Abstract

OBJECTIVES:

Major histocompatibility complex (MHC) class II-mediated priming of T and B lymphocytes is a central element of autoimmunity in systemic lupus erythematosus (SLE) and lupus nephritis. The cysteine protease cathepsin S degrades the invariant peptide chain during MHC II assembly with antigenic peptide in antigen-presenting cells; therefore, we hypothesised that cathepsin S inhibition would be therapeutic in SLE.

METHODS:

We developed a highly specific small molecule, orally available, cathepsin S antagonist, RO5461111, with suitable pharmacodynamic and pharmacokinetic properties that efficiently suppressed antigen-specific T cell and B cell priming in vitro and in vivo.

RESULTS:

When given to MRL-Fas(lpr) mice with SLE and lupus nephritis, RO5461111 significantly reduced the activation of spleen dendritic cells and the subsequent expansion and activation of CD4 T cells and CD4/CD8 double-negative T cells. Cathepsin S inhibition impaired the spatial organisation of germinal centres, suppressed follicular B cell maturation to plasma cells and Ig class switch. This reversed hypergammaglobulinemia and significantly suppressed the plasma levels of numerous IgG (but not IgM) autoantibodies below baseline, including anti-dsDNA. This effect was associated with less glomerular IgG deposits, which protected kidneys from lupus nephritis.

CONCLUSIONS:

Together, cathepsin S promotes SLE by driving MHC class II-mediated T and B cell priming, germinal centre formation and B cell maturation towards plasma cells. These afferent immune pathways can be specifically reversed with the cathepsin S antagonist RO5461111, which prevents lupus nephritis progression even when given after disease onset. This novel therapeutic strategy could correct a common pathomechanism of SLE and other immune complex-related autoimmune diseases.

KEYWORDS:

Autoantibodies; Autoimmune Diseases; Systemic Lupus Erythematosus; T Cells; Treatment

PMID:
24300027
DOI:
10.1136/annrheumdis-2013-203717
[Indexed for MEDLINE]
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