An orally active, primate selective antagonist of LFA-1 inhibits delayed-type hypersensitivity in a humanized-mouse model
| Autor: | Sudha Desai, Patricia L. Reilly, Deborah D. Jeanfavre, Gerald Nabozny, Terence A. Kelly, Lemieux Rene M, Maret Panzenbeck |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
medicine.drug_class
Administration Oral Mice SCID In Vitro Techniques Pharmacology Biology Peripheral blood mononuclear cell Major Histocompatibility Complex Mice Tetanus Toxin Antigen medicine Animals Edema Hypersensitivity Delayed Lymphocyte function-associated antigen 1 Cell Proliferation Dose-Response Relationship Drug Imidazoles Toxoid Antagonist Antibodies Monoclonal Receptor antagonist Lymphocyte Function-Associated Antigen-1 Mice Inbred C57BL Delayed hypersensitivity Models Animal Immunology Humanized mouse Leukocytes Mononuclear Female Immunosuppressive Agents |
| Zdroj: | European Journal of Pharmacology. 534:233-240 |
| ISSN: | 0014-2999 |
| Popis: | 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 7-10x10(6) 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 (P0.05). 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 approximately 1 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect