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Similarly the contribution of the LFA-1/ICAM interaction to the disease pathophysiology has not been overlooked. Clinical trials with a humanized anti-LFA-1 antibody (efalizumab) in psoriasis have underscored the importance of this axis in the recruitment of activated T cells to cutaneous sites. In mouse models of colitis, either deletion of the ICAM gene or downregulation of expression by antisense oligonucleotides103 reduces the extent of inflammation. Two series of synthetic allosteric antagonists have emerged from the finding that the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin binds to the I-domain allosteric sites of the CD11a subunit of LFA-1, locking its conformation in a low-affinity state and preventing its binding to ICAM-1. The a1 allosteric antagonists, which bind and stabilize the closed conformation of the CD11a I domain, include BIRT-377 (45) (Kd = 25.8 nM) and LFA-703 (46) as well as compounds such as 47105 (IC50 = 85 nM) and 48106 (IC50 = 4nM). There is significant structural diversity in the literature and further studies are warranted to determine the value of this axis in the modulation of leukocyte extravasation under conditions of inflammation.

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