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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1530-1539.
Prepublished online as a Blood First Edition Paper on May 10, 2007; DOI 10.1182/blood-2006-10-048173.
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Submitted October 2, 2006
Accepted April 21, 2007
The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations
Hongbo Wang, Bartosz Grzywacz, David Sukovich, Valarie McCullar, Qing Cao, Alisa B. Lee, Bruce R. Blazar, David N Cornfield, Jeffrey S. Miller, and Michael R. Verneris*
Dept of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, United States
Dept of Medicine, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, United States
Biostatistics Shared Resources, Cancer Center, University of Minnesota, Minneapolis, MN
Dept of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
* Corresponding author; email: verneris{at}umn.edu.
Cyclosporin A (CSA) is commonly used to prevent graft-vs-host disease. The influence of CSA on T cell function has been extensively investigated however; the effect of CSA on NK cells is less understood. NK cells were cultured with IL-2 and IL-15 ± CSA for 1 week. Compared to controls, CSA treated cultures showed fewer CD56+CD16+KIR+ NK cells and a reciprocal increase in CD56+CD16-KIR- cells. These changes were mainly due to a reduced proliferation of the CD56dim NK cell subpopulation and a relative resistance of CD56bright NK cells to CSA. Following co-culture with K562 targets, CSA exposed NK cells differed from controls and lacked Ca2+ oscillations, NFAT dephosphorylation and NFAT nuclear translocation. NK cells cultured in CSA retained cytotoxicity against K562, Raji and KIR ligand expressing lymphoblastoid cells. NK cells cultured in CSA showed increases in NKp30 and reductions in NKp44 and NKG2D. Following IL-12 and IL-18 stimulation, CSA treated NK cells showed more IFN- producing cells. Using in vitro NK cell differentiation, progenitor cells gave rise to more CD56+KIR- NK cells in the presence of CSA than controls. Collectively, these studies show that CSA influences NK cell function and phenotype which may have important implications for graft-vs-leukemia effects.
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