Regulation of Anti-HLA Antibody-Dependent Natural Killer Cell Activation by Immunosuppressive Agents

Abstract

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 ADCC-mediated 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.

Tocilizumab (Anti-IL-6R) Suppressed TNFα Production by Human Monocytes in an In Vitro Model of Anti-HLA Antibody-Induced Antibody-Dependent Cellular Cytotoxicity

“…7-10 In this study, we assessed a possibility that other CD16 bearing cells, monocytes, and CD8+ T cells, were capable of antibody-mediated cell activation, resulting in cytokine production in the in vitro ADCC. We found that, IFNγ, TNFα, and IL-6–producing cells were significantly elevated in the ADCC compared to MLR and controls.…”

“…9,10 Briefly, pooled PBMCs isolated from blood of 5 normal individuals and then irradiated (PBMCx) were preincubated with HS (ADCC condition) or normal sera (NS, mixed lymphocyte reaction [MLR] condition), and the antibody-coated PBMCx were used as stimulator cells. HS sera was prepared by pooling sera from 70 end-stage renal disease HS patients with PRA greater than 50% and the same HS sera was used for all experiments in this study.…”

“…7-9 We have also reported that the antibody-mediated NK cell activation was inhibited by calcineurin inhibitors and steroid in the in vitro ADCC and suggested that NK cell activation and their cytokine production via ADCC are likely important in mediating AMR, and may represent a newly recognized opportunity for modification of antibody-mediated allograft injury. 10 In addition to NK cells, primary cells for ADCC, other CD16 bearing cells, monocytes and CD8+ T cells, could also be involved in ADCC and cytokine production such as IFNγ, TNFα and/or IL-6.…”

MHC class I signaling: new functional perspectives for an old molecule

“…In human studies, NK-cell transcripts and intravascular accumulation of NK cells have been detected in kidney allografts with DSA and C4d negative chronic AMR (74). Shin and colleagues recently have shown that the calcineurin inhibitors, tacrolimus and cyclosporin A, in combination with prednisone synergistically suppress NK cell IFNγ production and degranulation significantly more than anti-metabolites, such as sirolimus or mycophenolate mofetil (75) (Figure 1). Given the NK cell signature of AMR in experimental models and in patients, it is possible that NK cells can be used as yet another tool to identify C4d negative rejection and may represent a therapeutic target to ameliorate AMR.…”

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…IFN-γ production by NK cells can be triggered by allogeneic target cells coated with alloantibody (139), and contributes to chronic rejection in murine models (129). Current immunosuppressive drugs incompletely inhibit NK cell-mediated alloreactivity (140).…”