The integrin lymphocyte function-associated antigen-1 (LFA-1) is a critical component in the effective trafficking of leukocytes and in facilitating subsequent antigen-specific interaction. The physiologic importance of LFA-1 in host defense is demonstrated through deficiency of this molecule in an inherited disease, LAD-I. By contrast, sustained and deregulated activation of LFA-1 is implicated in the pathogenesis of autoimmune and inflammatory diseases. Antagonists to LFA-1, including small-molecule compounds and monoclonal antibodies (mAbs), have been developed as anti-inflammatory agents. LFA-1 transduces signals bi-directionally across the plasma membrane by global conformational changes. At least two classes of potent small-molecule LFA-1 inhibitors have been identified. One class of inhibitors stabilizes LFA-1 in the inactive conformation whereas the other induces the active conformation. The mode of action and impact on signal transmission of these inhibitors are of great interest not only for designing second-generation antagonists with improved therapeutic potency but also for better understanding of mechanism of integrin activation. We will determine the mechanism of the small-molecule antagonists and define their effects on the signal transmission coupled to integrin conformation. Therapeutic mAbs to LFA-1, including efalizumab currently used for the treatment of psoriasis, bind non-selectively to the inactive and active conformers of LFA-1. As only the active form binds ligand, selective inhibition of the active LFA-1 would be sufficient to block its adhesive function and should exhibit advantages over non-selective agents as therapeutics in vivo. We will develop mAbs that preferentially bind and block the active LFA-1 by selecting human antibody libraries in vitro with the ligand-binding domain of LFA-1 locked in the high-affinity conformation. The active LFA-1-selective mAbs will be used for blocking ligand binding as well as probing the active LFA-1 on the cell surface in leukocyte migration and formation of immunological synapse.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Nabavi, Nasrin N
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Immune Disease Institute, Inc.
United States
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Dearling, Jason L J; Park, Eun Jeong; Dunning, Patricia et al. (2010) Detection of intestinal inflammation by MicroPET imaging using a (64)Cu-labeled anti-beta(7) integrin antibody. Inflamm Bowel Dis 16:1458-66
Yuki, Koichi; Astrof, Nathan S; Bracken, Clay et al. (2010) Sevoflurane binds and allosterically blocks integrin lymphocyte function-associated antigen-1. Anesthesiology 113:600-9
Kim, Sang-Soo; Peer, Dan; Kumar, Priti et al. (2010) RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Mol Ther 18:370-6
Park, Eun Jeong; Peixoto, Antonio; Imai, Yoichi et al. (2010) Distinct roles for LFA-1 affinity regulation during T-cell adhesion, diapedesis, and interstitial migration in lymph nodes. Blood 115:1572-81
Peer, Dan; Shimaoka, Motomu (2009) Systemic siRNA delivery to leukocyte-implicated diseases. Cell Cycle 8:853-9
Zhang, Hongmin; Liu, Jin-Huan; Yang, Wei et al. (2009) Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1. Proc Natl Acad Sci U S A 106:18345-50
Zhang, Hongmin; Astrof, Nathan S; Liu, Jin-Huan et al. (2009) Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems. FASEB J 23:2735-40
Yuki, Koichi; Astrof, Nathan S; Bracken, Clay et al. (2008) The volatile anesthetic isoflurane perturbs conformational activation of integrin LFA-1 by binding to the allosteric regulatory cavity. FASEB J 22:4109-16
Peer, Dan; Park, Eun Jeong; Morishita, Yoshiyuki et al. (2008) Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319:627-30
Shimaoka, M; Park, E J (2008) Advances in understanding sepsis. Eur J Anaesthesiol Suppl 42:146-53

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