Weitz-Schmidt Gabriele, Chreng Stéphanie, Riek Simone
Department of Autoimmunity, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Mol Pharmacol. 2009 Feb;75(2):355-62. doi: 10.1124/mol.108.051169. Epub 2008 Oct 27.
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.
自然杀伤（NK）细胞被认为在多种疾病病理过程中发挥重要作用，包括移植排斥和自身免疫。目前已知的治疗方法中，没有一种能有效干扰NK细胞活性。在此，我们首次证明，与其他免疫抑制剂相比，整合素淋巴细胞功能相关抗原-1（LFA-1）的低分子量抑制剂能在体外轻易阻断NK细胞的黏附、激活及NK细胞介导的细胞溶解。这些效应与实现LFA-1抑制的变构机制类型无关。此外，我们描述了一种简单的非放射性全血检测方法，该方法应适用于临床实践中监测NK细胞的激活。综上所述，我们的研究强调了LFA-1在NK细胞效应功能中的重要性，并表明变构LFA-1抑制剂可能成为进一步阐明NK细胞调节在免疫疾病中治疗潜力的重要工具。
