title: Natural Killer Cells Mediate Long-term Kidney Allograft Injury.
abstract: BACKGROUND
  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 natural killer (NK) cells are cytotoxic to tubular epithelial cells and contribute to acute kidney ischemia-reperfusion injury. The role of NK cells in kidney allograft rejection has not been studied.
  
  
  METHODS
  A "parent to F1" kidney transplant model was used to study NK cell-mediated transplant rejection.
  
  
  RESULTS
  The C57BL/6 kidneys were transplanted into fully nephrectomized CB6F1 (C57BL/6 x BALB/c) mice. Serum creatinine levels increased from baseline (18.8 ± 5.0 μmol/L to 37.2 ± 5.9 μmol/L, P < 0.001) at 60 days after transplantation. B6Rag-to-CB6F1Rag (B6RagxBALB/cRag) recipients, which lack T and B cells but retain NK cells, showed similar levels of kidney dysfunction 65 days after transplantation (creatinine, 33.8 ± 7.9 μmol/L vs 17.5 ± 5.1 μmol/L in nontransplant Rag mice, P < 0.05). Importantly, depletion of NK cells in Rag1 recipients inhibited kidney injury (24.6 ± 5.5 μmol/L, P < 0.05). Osteopontin, which can activate NK cells to mediate tubular epithelial cell death in vitro, was highly expressed in 60 days kidney grafts. Osteopontin null kidney grafts had reduced injury after transplantation into CB6F1 mice (17.7 ± 3.1 μmol/L, P < 0.001).
  
  
  CONCLUSIONS
  Collectively, these data demonstrate for the first time that independent of T and B cells, NK cells have a critical role in mediating long-term transplant kidney injury. Specific therapeutic strategies that target NK cells in addition to conventional immunosuppression may be required to attenuate chronic kidney transplant injury.
authors.affiliation: 1 Matthew Mailing Centre for Translational Transplant Studies, London Health Sciences Centre, London, Ontario, Canada. 2 Department of Medicine, Western University, London, Ontario, Canada. 3 Department of Pathology, Western University, London, Ontario, Canada. 4 Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
authors.forename: Xuyan
authors.initials: X
authors.lastname: Huang
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.forename: Arthur
authors.initials: A
authors.lastname: Lau
authors.forename: Ziqin
authors.initials: Z
authors.lastname: Yin
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Aaron
authors.initials: A
authors.lastname: Haig
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
mesh_terms: D064591:Allografts; D000818:Animals; D017209:Apoptosis; D006084:Graft Rejection; D016030:Kidney Transplantation / Q000009:adverse effects*; D007684:Kidney Tubules / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000032:analysis; D053495:Osteopontin / Q000502:physiology
chemical_list: C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053495:Osteopontin