NK Cells Mediate Chronic Kidney Allograft Injury.

Abstract

Chronic allograft injury remains the leading cause of late kidney graft loss despite improvements in immunosuppressive drugs and a reduction in acute T cell mediated rejection. We have recently demonstrated that NK cells are cytotoxic to tubular epithelial cells (TECs) and contribute to acute kidney ischemia-reperfusion injury (IRI). The role of NK cells in kidney allograft rejection has not been studied. A parent to F1 transplant model in which T cell tolerance is present, was utilized for these studies. C57BL/6 kidneys were transplanted into fully nephrectomized F1 (C57BL/6 x BALB/c, CB6F1) mice. Serum creatinine levels increased from baseline (18.8+5.0 umol/l to 37.2±5.9 umol/l, P<0.001) at 60 days post transplantation. In further support of this, in B6Rag-/--to- CB6F1Rag-/- (B6Rag-/-xBALB/cRag-/-) F1 kidney transplants which lack T and B cells but retain NK cells, similar levels of kidney dysfunction were observed 65 days post transplant (creatinine: 33.8+7.9 umol/l vs. 17.5+5.1 umol/l in non-transplant Rag-/- mice, P<0.05). Depletion of NK cells in Rag1-/- mice prevented kidney injury (24.6±5.5 umol/l, p<0.05). Interestingly, osteopontin (OPN) was highly expressed in 60 days kidney grafts, and OPN deficiency in kidney graft had reduced chronic injury after transplantation (17.7+3.1 umol/l, P<0.001). OPN activated NK cells can mediate TEC death in vitro. In conclusion, these data demonstrate for the first time a critical role for NK cells in mediating chronic kidney injury in transplantation, which is independent of T and B cells. It may require specific therapeutic strategies to attenuate NK cells' contribution to chronic kidney injury.