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 IC(50)=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 x 10(6)) from tetanus-sensitized donors were co-injected with tetanus toxoid (0.25 Lf) 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 approximately 18 mg/kg. Compound III, a less active analogue (molecular IC50>20 microM) 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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Authors | Sudha N Desai, Della M White, Kathryn M O'shea, Maryanne L Brown, Charles L Cywin, Denice M Spero, Maret J Panzenbeck |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 538
Issue 1-3
Pg. 168-74
(May 24 2006)
ISSN: 0014-2999 [Print] Netherlands |
PMID | 16631730
(Publication Type: Journal Article)
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Chemical References |
- Enzyme Inhibitors
- Cathepsins
- cathepsin S
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Topics |
- Administration, Oral
- Animals
- Biological Availability
- Cathepsins
(antagonists & inhibitors, genetics)
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(chemistry, pharmacokinetics, pharmacology)
- Hypersensitivity, Delayed
(immunology, pathology, prevention & control)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Structure
- Structure-Activity Relationship
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