Natural Killer Cells Promote Kidney Graft Rejection Independently of Cyclosporine A Therapy

Abstract

Natural Killer (NK) cells have recently been recognized as key players in antibody-mediated chronic allograft failure, thus requiring a comprehensive understanding whether NK cells can escape conventional immunosuppressive regimens. Influence of cyclosporine A (CyA) on NK cell function was studied in a mouse model of allogeneic kidney transplantation (KTX, BALB/c to C57BL/6). Recipients were treated daily with CyA (10 mg/kg) for seven or 14 days for long term survival (day 56). Administration of CyA in recipients resulted in significantly reduced frequencies of intragraft and splenic CD8+ T cells, whereas the latter illustrated reduced IFNγ production. In contrast, intragraft and splenic NK cell frequencies remained unaffected in CyA recipients and IFNγ production and degranulation of NK cells were not reduced as compared with controls. Depletion of NK cells in combination with CyA resulted in an improvement in kidney function until day 7 and prolonged graft survival until day 56 as compared to untreated controls. Surviving animals demonstrated higher intragraft frequencies of proliferating CD4+FoxP3+Ki67+ regulatory T (TREG) cells as well as higher frequencies of CD8+CD122+ TREG. We here demonstrate that NK cell depletion combined with CyA synergistically improves graft function and prolongs graft survival, suggesting that NK cell targeting constitutes a novel approach for improving KTX outcomes.

Chronic histiocytic intervillositis: A breakdown in immune tolerance comparable to allograft rejection?

“…101 AMR leads to graft loss via complement deposition, recruitment of NK cells, monocytes and macrophages which contribute towards fibrin formation, endothelial cell damage and eventually interruption of vascular function. 98,102 Anti-HLA antibodies identified in CHI could be likened to these DSAs, especially as complement, monocytes and macrophages also appear to play a key role in its pathophysiology. 4,63 However, as the placenta is known to express only the least polymorphic of HLA molecules with low immunogenicity, it is unclear how anti-HLA antibodies may be detrimental when not deemed so in normal healthy pregnancy.…”

Recipient myeloperoxidase-producing cells regulate antibody-mediated acute versus chronic kidney allograft rejection

“…Most transplant patients maintain a course of immunosuppression to inhibit donor-reactive T cell responses that includes an anti-proliferative drug and a calcineurin inhibitor. Whether these immunosuppressive drugs inhibit NK cell activation is not as clear with in vitro and in vivo studies yielding unclear conclusions their efficacy on NK cell activation (56)(57)(58). The results of the current study suggest that identification of myeloid cell targets will also attenuate acute ABMR.…”

Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity

“…In solid organ transplantation, a large number of cells expressing foreign human leukocyte antigens (HLA) are introduced into the transplant recipient. Mouse models have shown that alloreactive NK cells can be a notable contributor to kidney allograft rejection ( 30 ). Further, alloreactive NK cells seemed to contribute allograft rejection in human liver transplantation ( 31 ).…”