The corticosteroid‐induced inhibitory effect on NK cell function reflects down‐regulation and/or dysfunction of triggering receptors involved in natural cytotoxicity

Abstract

Corticosteroids are known to inhibit NK cell functions. However no information is available on whether such inhibition may affect the expression and/or the function of receptors involved in NK cell activation. In an attempt to analyze this point, we studied peripheral blood NK cells isolated from pediatric patients undergoing allogeneic BM transplantation. NK cells were analyzed before, during and after methylprednisolone administration to treat acute graftversus-host disease. In NK cells freshly isolated from peripheral blood during methylprednisolone treatment, the surface expression of activating receptors, particularly NKp46 and NKp30, was consistently reduced. Such impaired expression could also be detected after 5 days of culture in IL-2. Such cultured NK cells also failed to express the IL-2-inducible NKp44 receptor. Accordingly, cytotoxicity against different tumor target cell lines was sharply reduced. The effect on NK cells isolated from healthy individuals and cultured in the presence of methylprednisolone was also analyzed. A similar inhibitory effect occurred in the expression of activating NK receptors. In addition, a sharp impairment of NK cytotoxicity against different tumor target cell lines or immature DC was detected.

Sequential recovery of NK cell receptor repertoire after allogeneic hematopoietic SCT

“…36 Moreover, as shown in clinical models, the use of methylprednisolone has a negative effect on NK cell cytotoxicity and the expression of the major activating receptors, including NKp30 and NKp44. 37 Therefore, results of our study, in the context of previous reports, indicate that the use of steroids should be avoided if NK cell alloreactivity is expected. In contrast, the beneficial effect of KIR-ligand incompatibility should be anticipated only in transplant cohorts with low risk of GVHD and other complications requiring administration of steroids.…”

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

“…49 Methylprednisolone has been shown to induce not only NK cell maturation but also to impair their cytotoxicity in vitro. 50,51 In vivo, prophylactic corticosteroids seemed to alter NK cell recovery after HSCT. 52 The similar results between related and unrelated HSCT, which we observed, suggest that antithymocyte globulin has a minor role in GvL effect, confirming previous reports.…”

A novel immunomodulatory mechanism of ribavirin in suppressing natural killer cell function

“…The FcγR + P815 cell line has been extensively used for mAb-mediated redirected killing assays using NK cells and mAbs capable of triggering their cytolytic functions [23,29]. This would allow us assess in a cytolytic assay the direct effect of ribavirin on the specific activity of NK trigerring receptors.…”