Desai Sudha N, White Della M, O'shea Kathryn M, Brown Maryanne L, Cywin Charles L, Spero Denice M, Panzenbeck Maret J
Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceutical Inc., 900 Ridgebury Road, Box 368, Ridgefield, CT 06877-0368, USA.
Eur J Pharmacol. 2006 May 24;538(1-3):168-74. doi: 10.1016/j.ejphar.2006.03.051. Epub 2006 Mar 28.
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.
组织蛋白酶S是一种主要组织相容性复合体（MHC）II类相关恒定链（Ii）降解酶，在诸如B细胞和树突状细胞等抗原呈递细胞中表达。这种酶对于MHC II类相关抗原加工及呈递给CD4(+) T细胞至关重要。化合物I是一种选择性、可逆且口服生物可利用的组织蛋白酶S抑制剂，其分子IC(50)=9 nM，最近已有报道。我们在迟发型超敏反应的转体内模型中测试了化合物I的作用。将来自破伤风致敏供体的人外周血单个核细胞（7 - 10×10(6)）与破伤风类毒素（0.25Lf）共同注射到C57Bl/6小鼠脚垫中。24小时时，观察到明显的脚垫肿胀（+0.024±0.001厘米），其特征为小鼠中性粒细胞和单核细胞的流入。单独注射外周血单个核细胞引起的肿胀可忽略不计（0.002±0.0002厘米）。抗人MHC II类（HLA - DR、DP、DQ）抗体（5毫克/千克，腹腔注射）抑制肿胀达91±7%，从而证明了人抗原呈递细胞在该模型中的作用。化合物I（10、30和100毫克/千克，口服）以约18毫克/千克的ED50抑制反应。活性较低的类似物化合物III（分子IC50>20 microM）无作用。此外，用10 nM化合物II（一种不可逆抑制剂，分子IC50=11 nM）对外周血单个核细胞进行预处理可抑制肿胀87±4%。这些发现支持了组织蛋白酶S在人类迟发型超敏反应中的作用。用化合物I抑制组织蛋白酶S可能对治疗类风湿性关节炎和多发性硬化症等人类自身免疫性疾病有用。
