Allosteric LFA-1 Inhibitors Modulate Natural Killer Cell Function

Abstract

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.

G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT

“…8 Further analysis of gene expression in NK cells by RT-PCR demonstrated that the TPI gene, but neither ubiquitin nor calreticulin genes, was downregulated by G-CSF treatment (Figure 6a). Table 1 lists the primers used in this study.…”

“…7 NK cell activity is also involved in a variety of pathologic conditions, such as autoimmune diseases and transplant rejection. 8 In particular, for hematopoietic SCT (HSCT) of leukemia patients, NK cells have a critical role in regulating immune responses, including GVHD and GVL effects. 8 HSCT, whether hematopoietic stem cells derived from the BM, cord blood or peripheral blood, is a medical strategy used for select patients with blood-and BMrelated diseases and certain types of cancers.…”

“…8 In particular, for hematopoietic SCT (HSCT) of leukemia patients, NK cells have a critical role in regulating immune responses, including GVHD and GVL effects. 8 HSCT, whether hematopoietic stem cells derived from the BM, cord blood or peripheral blood, is a medical strategy used for select patients with blood-and BMrelated diseases and certain types of cancers. 9 Although autologous HSCT is not suitable for most patients, various types of allogenic (allo)-HSCT, including unrelated donorand haploidentical allo-HSCT, appear to improve chances for successful treatment compared with no transplantation.…”

Identifizierung und Strukturbestimmung eines niedermolekularen Aktivators der LFA‐1/ICAM‐1‐Bindung

“…Die Bindungsachse zwischen LFA-1 und ICAM-1 wurde aus diesem Grund bereits früher als mçglicher Ansatzpunkt für die Medikamententwicklung beschrieben. [4][5][6][7] Allerdings stellt die Konformationsänderung von niedrig affinen zu hochaffinen Zuständen, die mit der Bindung von LFA-1 an ICAM-1 einhergeht, eine erhebliche Hürde für die Konstruktion von LFA-1-Inhibitoren dar. [8,9] Obwohl die Inhibierung von Protein-Protein-Interaktionen (PPIs) mittels kleiner Moleküle lange Zeit als die ultimative Herausforderung in der Wirkstoffentwicklung galt, wurden nur sehr wenige Beispiele für solche PPI-Inhibitoren beschrieben.…”

Antibody Against Integrin Lymphocyte Function-Associated Antigen 1 Inhibits HIV Type 1 Infection in Primary Cells Through Caspase-8-Mediated Apoptosis

“…65 These results are in line with data from recent studies showing that small molecule inhibitors of LFA-1/ICAM-1 interactions prevent cell-to-cell adhesion and HIV infection. 66,67 The fact that the anti-LFA-1 antibody could be added to T cell cultures 24 h after adding HIV-1 indicated that the antibody was possibly mediating its effect through a postentry mechanism. Considering that apoptosis is an important FIG.…”