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* Respiratory and Inflammation Center of Excellence for Drug Discovery,
Chemical Development,
Discovery Statistics, and
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, PA 19406; and
¶ Microbial, Musculoskeletal, and Proliferative Diseases Center of Excellence for Drug Discovery,
|| Research Statistics Unit, and
# Screening and Compound Profiling, GlaxoSmithKline, Collegeville, PA 19426
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-1β and TNF-
. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Patricia Podolin, GlaxoSmithKline, Mail Code UW2532, 709 Swedeland Road, King of Prussia, PA 19406. E-mail address: patty_podolin{at}gsk.com
2 Current address: Thomas Jefferson University, Philadelphia, PA 19107.
3 Current address: Thomas Jefferson University, Philadelphia, PA 19107.
4 Current address: Merck Research Laboratories, West Point, PA 19486.
5 Current address: Drexel University, Philadelphia, PA 19104.
6 Abbreviations used in this paper: RA, rheumatoid arthritis; cTEC, cortical thymic epithelial cells; CIA, collagen-induced arthritis; EAE, experimental autoimmune encephalomyelitis; DPBS, Dulbecco’s PBS; MBP, myelin basic protein; LNC, lymph node cells; AUC, area under the curve.
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