Regulation of anti-HLA antibody-dependent natural killer cell activation by immunosuppressive agents.

Background. It was demonstrated that human natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC)-like mechanism, increase IFNF production after exposure to alloantigens. This finding was associated with an increased risk for antibody-mediated rejection (ABMR). Although the effects of various immunosuppressive drugs on T cells and B cells have been extensively studied, their effects on NK cells are less clear. This study reports the effect of immunosuppressive agents on antibody-mediated NK cell activation in vitro. Methods. Whole blood from normal individuals was incubated with irradiated peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody+ sera (in vitro ADCC), with or without immunosuppressive agents. The %IFNF+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated by flow cytometry. Results. Cyclosporine A and tacrolimus significantly reduced IFNF production in a dose-dependent manner (53%Y83%), but showed minimal effect on degranulation (20%). Prednisone significantly reduced both IFNF production and degranulation (50%Y66% reduction at maximum therapeutic levels). Calcineurin inhibitors (CNIs) in combination with prednisone additively suppressed IFNF production and degranulation. The effect of sirolimus or mycophenolate mofetil on NK cells was minimal. Conclusions. These results suggest that potent suppressive effects of CNIs and prednisone on antibody-mediated NK cell activation may contribute to the reduction of ADCC in sensitized patients and possibly reduce the risk for ADCCmediated ABMR. These further underscore the importance of medication compliance in prevention of ABMR and possibly chronic rejection, and suggest that ADCC-mediated injury may increase in strategies aimed at CNI or steroid minimization or avoidance.