A small-molecule antagonist of LFA-1 blocks a conformational change important for LFA-1 function

Abstract: Lymphocyte function-associated antigen (LFA)-1/intercellular adhesion molecule (ICAM)-1 in-teractions mediate several important steps in the evolution of an immune response. LFA-1 is nor-mally expressed in a quiescent state on the surface of leukocytes and interacts weakly with its ligands ICAM-1,-2, and-3. LFA-1 activity may be regu-lated by receptor clustering and by increasing the affinity of LFA-1 for its ligands. Affinity modulation of LFA-1 has been shown to occur via a conforma-tional change in the LFA-1 heterodimer that can be detected by using monoclonal antibody 24 (mAb24). We have recently described a small-mol-ecule antagonist of LFA-1, BIRT 377, that dem-onstrates selective in vitro and in vivo inhibition of LFA-1/ICAM-1-mediated binding events. We now demonstrate that BIRT 377 blocks the induction of the mAb24 reporter epitope on LFA-1 on the surface of SKW-3 cells treated with various ago-nists known to induce high-affinity LFA-1. These data imply that BIRT 377 exerts its inhibitory effects by preventing up-regulation of LFA-1 to its high-affinity conformation. J. Leukoc. Biol. 70: 329–334; 2001. Key Words: adhesion molecules z inflammation z cell-cell inter-actions z FACS z integrin z mAb epitop