The role of leukocyte function-associated antigen-1 in animal models of inflammation

• Published in: European journal of pharmacology 2001-10, Vol.429 (1), p.297-302
• Main Authors: Winquist, Raymond J, Desai, Sudha, Fogal, Stephen, Haynes, Nancy A, Nabozny, Gerald H, Reilly, Patricia L, Souza, Donald, Panzenbeck, Maret
• Format: Article
• Language: English
• Subjects: Animals; Antigen presentation; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell adhesion; delayed-type; Disease Models, Animal; Humans; Hypersensitivity; Hypersensitivity, Delayed - drug therapy; Hypersensitivity, Delayed - immunology; Imidazoles - pharmacology; Imidazolidines; Immunoglobulin G - biosynthesis; Immunosuppressive Agents - pharmacology; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Leukocyte; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; LFA-1 (leukocyte function-associated antigen-1); Lymphocyte Function-Associated Antigen-1 - physiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; mouse; Pharmacology. Drug treatments; Saimiri; SCID; Staphylococcal enterotoxin B; T cell; Trans-vivo
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01328-0

Both preclinical and clinical data have identified leukocyte function-associated antigen-1 (LFA-1) as an important component of inflammatory disease states. We evaluated small molecule inhibitors of this glycoprotein in several animal models in which the inflammatory process is dependent on human or non-human primate LFA-1. ( R)-5(4-bromobenzyl)-3(3,5-dichlorophenyl)-1,5-dimethylimidazolidine-2,4-dione, BIRT 377, effectively suppressed the production of human immunoglobulin (IgG) following reconstitution of severe combined immunodeficient (SCID) mice with human peripheral blood mononuclear cells. The BIRT 377 analog, BIX 642, inhibited the cellular infiltrate and increase in skin thickness associated with the delayed-type hypersensitivity reaction in previously immunized squirrel monkeys challenged with antigen. BIX 642 also inhibited the trans-vivo delayed-type hypersensitivity response in the footpads of SCID mice injected with human peripheral blood mononuclear cells and donor-sensitive antigen. These results demonstrate the efficacy of small molecule inhibitors of LFA-1 in preclinical models of inflammation dependent on human or non-human primate LFA-1.