Allosteric LFA-1 Inhibitors Modulate Natural Killer Cell Function

• Published in: Molecular pharmacology Vol. 75; no. 2; pp. 355 - 362
• Main Authors: Gabriele Weitz-Schmidt, Stéphanie Chreng, Simone Riek
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.02.2009
• Subjects: Biophysical Phenomena; Cell Adhesion - drug effects; Cell Adhesion - physiology; Humans; K562 Cells; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - physiology; Lymphocyte Function-Associated Antigen-1 - drug effects; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphocyte Function-Associated Antigen-1 - physiology; Signal Transduction - physiology
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.108.051169

Natural killer (NK) cells are believed to play an important role in a variety of disease pathologies, including transplant rejection and autoimmunity. None of the therapeutic modalities currently available are known to potently interfere with NK cell activity. Here we demonstrate for the first time that low molecular weight inhibitors of the integrin lymphocyte function-associated antigen-1 (LFA-1) readily block NK cell adhesion, activation, and NK cell-mediated cytolysis in vitro, in contrast to other immunosuppressive agents. These effects were independent of the type of allosteric mechanism by which LFA-1 inhibition was achieved. In addition, we describe a simple, nonradioactive whole-blood assay that should be suitable to monitor NK cell activation in clinical practice. Taken together, our study underlines the importance of LFA-1 in NK cell effector functions and indicates that allosteric LFA-1 inhibitors may become important tools to further elucidate the therapeutic potential of NK cell modulation in immunological diseases.