The role of leukocyte function-associated antigen-1 in animal models of inflammation.
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.
Winquist
R J
RJ
Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877, USA. Rwinquis@rdg.boehringer-ingelheim.com
Desai
S
S
Fogal
S
S
Haynes
N A
NA
Nabozny
G H
GH
Reilly
P L
PL
Souza
D
D
Panzenbeck
M
M
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007074:Immunoglobulin G / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012453:Saimiri
C400461:BIRT 377; D007093:Imidazoles; D048289:Imidazolidines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1