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

Both preclinical and clinical data have identified leukocyte function-assoc iated antigen-1 (LFA-1) as an important component of inflammatory disease s tates. We evaluated small molecule inhibitors of this glycoprotein in sever al 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- d imethylimidazolidine-2,4-dione, BIRT 377, effectively suppressed the produc tion of human immunoglobulin (IgG) following reconstitution of severe combi ned immuno deficient (SCID) mice with human peripheral blood mononuclear ce lls. The BIRT 377 analog, BIX 642, inhibited the cellular infiltrate and in crease 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 respons e in the footpads of SCID mice injected with human peripheral blood mononuc lear cells and donor-sensitive antigen. These results demonstrate the effic acy of small molecule inhibitors of LFA-1 in preclinical models of inflamma tion dependent on human or non-human primate LFA-1. (C) 2001 Elsevier Scien ce B.V. All rights reserved.