H- 01: lymphocytes
H- 01: T-cell biology and physiology
H- 15: Late rejection
H- 15: Transplant allograft dysfunction
Natural Killer Cells Mediate Long-term Kidney Allograft Injury
Zhang, Zhu-Xu; Huang, Xuyan; Jiang, Jifu; Lau, Arthur; Yin, Ziqin; Liu, Weihua; Haig, Aaron; Jevnikar,
Anthony M.
Journal : Transplantation
Year : 2015 / Month : May
Volume 99
Pages : 916–924
DOI: 10.1097/TP.0000000000000665
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−/− (B6Rag−/−xBALB/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.
COMMENTS
This is the most recent article on mechanisms involved in chronic kidney transplant rejection. A well done
experimentation in mice demonstrates the respective role of B, T and Natural Killer cells.
These data deserve consideration not only for understanding more precisely the pathogenesis of chronic
rejection, but also to identify special targets for improving the choice of immunosuppressive drugs.
Pr. Jacques CHANARD
Professor of Nephrology