Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2537493 | European Journal of Pharmacology | 2006 | 8 Pages |
Abstract
Compound I, a novel small molecule antagonist (Kd = 6 nM) of human lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) was tested for activity in a humanized mouse model of delayed-type hypersensitivity (trans vivo delayed-type hypersensitivity). Trans vivo delayed-type hypersensitivity is a model for testing compounds with human targets in mice. Tetanus toxoid and 7-10 Ã 106 human peripheral blood mononuclear cells from tetanus-sensitized donors were coinjected into footpads of naive mice. Footpads were measured before and 24 h later. Injection of peripheral blood mononuclear cells plus antigen resulted in swelling of 0.178-0.254 mm, significantly greater than peripheral blood mononuclear cells or tetanus toxoid alone (P < 0.05). Preincubation of peripheral blood mononuclear cells with anti-human major histocompatibility complex class II (MHCII) or anti-human LFA-1 monoclonal antibody (mAb), but not anti-mouse MHCII or anti-mouse LFA-1 mAb, significantly inhibited the response. Compound I inhibited footpad swelling in a dose related manner (0.1-100 mg/kg, p.o.; ED50 â¼1 mg/kg), whereas its enantiomer had no effect. These data demonstrate the oral efficacy of a novel antagonist of LFA-1 in trans vivo delayed-type hypersensitivity.
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Authors
Maret J. Panzenbeck, Deborah D. Jeanfavre, Terence A. Kelly, Rene Lemieux, Gerald Nabozny, Patricia L. Reilly, Sudha Desai,