Background Natural killer (NK) cells expressing CD94/NKG2A, an inhibitory receptor binding HLA-E, accumulate in the inflamed joints of Rheumatoid Arthritis (RA) patients . At this site they frequently interact with multiple inflammatory cell subsets. Recent data indicate that NK cells may play a role in RA disease pathology by their capacity to trigger the differentiation of monocytes into osteoclasts .
Objectives The aim of this study was to determine whether blocking the CD94/NKG2A interactions with HLA-E using a novel therapeutic mAb affects osteoclastogenesis in ex vivo RA synovial fluid mononuclear cell (SFMC) cultures.
Methods To study osteoclastogenesis and in vitro bone mineral erosion, SFMCs were cultured in the absence or presence of IL-15. These cultures were treated with and without the antagonistic humanized anti-NKG2A mAb (NNC141-0100) followed by analysis of the formation of TRAP+ multinucleated osteoclasts and functional bone mineral erosion. To measure cytokine release, supernatants were harvested at various time points followed by detection using a Bioplex array.
Results Blocking CD94/NKG2A in SFMC cultures resulted in a significantly reduced formation of TRAP+ multinucleated cells (p<0.01, n=14), reduced bone mineral erosion (p<0.03, n=5), and reduced IL-6 levels (p<0.01, n=11).
Conclusions This study shows that blocking CD94/NKG2A with anti-NKG2A mAb NNC141-0100 that is currently being developed for the treatment of RA, leads to suppression of osteoclast formation and subsequent bone erosion, as well as a reduction in IL-6 levels in vitro. Based on these findings, we propose that anti-NKG2A therapy may have a beneficial effect in vivo in RA patients.
Teixeira de Matos C et al. Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology. 2007 Oct;122(2):291-301.
Söderström K et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13028-33.
Disclosure of Interest K. Söderström Employee of: novo nordisk, Y. Sundström Grant/Research support from: novo nordisk, L. Berg Grant/Research support from: novo nordisk, D. Schepis Grant/Research support from: novo nordisk, E. Galsgaard Shareholder of: novo nordisk, Employee of: novo nordisk, L. Klareskog Grant/Research support from: novo nordisk, N. Wagtmann Shareholder of: novo nordisk, Employee of: novo nordisk
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