The unexpected effect of cyclosporin A on CD56+CD16− and CD56+CD16+ natural killer cell subpopulations

Abstract

Cyclosporin A (CSA) is commonly used to prevent graft-versus-host disease. The influence of CSA on T-cell function has been extensively investigated; however, the effect of CSA on natural killer (NK) cells is less understood. NK cells were cultured with IL-2 and IL-15 with and without CSA for 1 week. Compared with controls, CSA-treated cultures showed fewer CD56+CD16+KIR+ NK cells and a reciprocal increase in CD56+CD16−KIR− cells. These changes were due mainly to a reduced proliferation of the CD56dim NK-cell subpopulation and a relative resistance of CD56bright NK cells to CSA. Following coculture with K562 targets, CSA-exposed NK cells differed from controls and lacked Ca2+ oscillations, nuclear factor of activated T cells (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-γ–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-versus-leukemia effects.

Licensed to Kill: Towards Natural Killer Cell Immunotherapy

“…Thus, as CD56 bright NK cells were still abundantly present in the CsA-treated cultures, in contrast to MPA-and Rapa-treated cultures, the IFN- production upon cytokine stimulation may largely be preserved after CsA treatment. This was confirmed in a study showing sustained IFN- production by CsA-treated NK cell cultures upon IL-12 and IL-18 stimulation (Wang et al, 2007), suggesting that IFN--mediated GVL reactivity after allogeneic SCT should remain intact when using CsA as GVHD prophylaxis. Our findings on the effect of CsA and MPA on the cytolytic response by in vitro cytokinestimulated NK cells are in concert with previous findings on this subject (Ohata et al, 2011).…”

Cyclosporin A Suspends Transplantation Reactions in the Marine SpongeMicrociona prolifera

“…Following receptor ligation free intracellular Ca 2ϩ increases, triggering a series of downstream events including the activation of calcineurin. It has been recently shown that CsA-treated NK cells exhibit an alteration of calcineurin activity that disrupts intracellular Ca 2ϩ patterns and blocks NFAT translocation (67). What effects this has on later stages of NK cell activation are not well understood.…”

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

“…Indeed, CsA pharmacodynamic effect on NK cells is distinct and allows NK cell cytotoxicity, 41 whereas it is impaired by MMF [42][43][44] or MTX. [45][46][47] Moreover, calcineurin inhibitors are the only immunosuppressive agents exerting their action by inhibiting interleukin-2 production.…”