An orally active reversible inhibitor of cathepsin S inhibits human trans vivo delayed-type hypersensitivity

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Abstract

Cathepsin S is a major histocompatibility complex (MHC) class II associated invariant chain (Ii) degrading enzyme expressed in antigen presenting cells such as B cells and dendritic cells. This enzyme is essential for MHC class II associated antigen processing and presentation to CD4+ T cells. Compound I, a selective, reversible and orally bioavailable, inhibitor of cathepsin S, with molecular IC50 = 9 nM, has been recently described. We have tested the effects of compound I in a trans vivo model of delayed-type hypersensitivity. Human peripheral blood mononuclear cells (7–10 × 106) from tetanus-sensitized donors were co-injected with tetanus toxoid (0.25Lf) into C57Bl/6 mouse footpads. At 24 h, significant footpad swelling (+0.024 ± 0.001 cm) characterized by an influx of mouse neutrophils and monocytes was observed. Injection of peripheral blood mononuclear cells alone caused negligible swelling (0.002 ± 0.0002 cm). Anti-human MHC class II (HLA-DR, DP, DQ) antibody (5 mg/kg, i.p.) inhibited the swelling 91 ± 7%, thus demonstrating a role of human antigen presenting cells in this model. Compound I (10, 30, and 100 mg/kg, p.o.) inhibited the response with an ED50 of ˜18 mg/kg. Compound III, a less active analogue (molecular IC50 > 20 μM) had no effect. Furthermore, pretreatment of peripheral blood mononuclear cells with 10 nM compound II, an irreversible inhibitor (molecular IC50 = 11 nM) inhibited swelling 87 ± 4%. These findings support the role of cathepsin S in human delayed-type hypersensitivity. Inhibition of cathepsin S with compound I may be useful in the treatment of human autoimmune diseases like rheumatoid arthritis and multiple sclerosis.

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