The roles of natural killer (NK) cells in organ transplant injury and rejection are largely unknown. This is of particular interest, because current immunosuppressive drugs used in clinical solid organ transplantation do not target NK cells. We aimed to study whether NK cells can induce allograft injury early after transplantation. We performed MHC mismatched kidney transplantation by implanting wild-type H-2^k CBA donor kidneys into T-cell/B-cell-null B6.Rag1^–/^– H-2^b recipients. We also studied CBA into CBA kidney isografts, Rag1^–/^– into Rag1^–/^– kidney isografts, and normal CBA or Rag1^–/^– kidneys as controls. Transplanted kidneys were harvested on day 7 post-transplant and analyzed by histopathology, immunohistochemistry, and Affymetrix gene expression microarrays. Apoptosis was visualized by cleaved caspase-3 immunohistochemistry. Intrarenal burden of NK cells and macrophages were quantified by immunostaining using Ly49G2 and CD68 antibodies, respectively. By histopathology, Rag1^–/^– allografts did not show rejection detected by conventional stains and were not different from controls. However, by microarrays Rag1^–/^– allografts displayed significantly increased expression of interferon-gamma gene, interferon-gamma inducible genes, and NK receptor genes when compared to normal kidneys, CBA isografts, and Rag1^–/^– isografts. By immunostaining, Rag1^–/^– allograft tissues displayed significantly higher numbers of NK cell infiltrates in the interstitium and increased cleaved caspase-3 (CC3) positive apoptotic tubular epithelial cells and glomerular cells in comparison to controls, including Rag1^–/^– isografts. The amounts of intragraft macrophages were not different among Rag1^–/^– allografts, Rag1^–/^– isografts, and CBA isografts.

Our results indicate that T- and B-cell deficient mouse kidney recipients display signs of kidney allograft injury associated with NK cell activation causing allograft parenchymal apoptotic cell death and intragraft production of interferon-gamma. Thus, findings in this model suggest that NK cells recognize missing self MHC in allograft tissues and are capable to induce early allograft injury.

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