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Transplantation. 2014 Aug 27;98(4):402-10. doi: 10.1097/TP.0000000000000237.

Serine protease inhibitor-6 inhibits granzyme B-mediated injury of renal tubular cells and promotes renal allograft survival.

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  • 11 Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre. 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. 5 Address correspondence to: Zhu-Xu Zhang and Anthony M. Jevnikar, Department of Medicine, University of Western Ontario, B4-231, 339 Windermere Road, London, Ontario, Canada N6A 5A5.



Protease inhibitor 9 (PI-9) is an intracellular serpin that specifically inhibits granzyme B, a cytotoxic serine protease found in the cytosolic granules of cytotoxic T lymphocytes and natural killer cells. Enhanced cortical expression of PI-9 has been observed in kidney allografts with subclinical rejection, suggesting that the tubular epithelial cell (TEC) expression of this protein may have a protective role and attenuate overt allograft rejection.


We demonstrate that TEC express SPI-6 protein, the murine homolog of PI-9, basally with a modest increase after cytokine exposure. Tubular epithelial cell expression of SPI-6 blocks granzyme B-mediated death because TEC from SPI-6 null kidneys have increased susceptibility to cytotoxic CD8+ cells in vitro. The role of SPI-6 was tested in a mouse kidney transplant model using SPI-6 null or wild type donor kidneys (H-2) into nephrectomized recipients (H-2). SPI-6 null kidney recipients demonstrated reduced renal function at day 8 after transplantation compared to controls (creatinine, 113±23 vs. 28±3 μmol/L; n=5; P<0.01), consistent with observed tubular injury and extensive mononuclear cell infiltration. Loss of donor kidney SPI-6 shortened graft survival time (20±19 vs. 66±33 days; n=8-10; P<0.001).


Our data show for the first time that resistance of kidney TEC to cytotoxic T-cell granzyme B-induced death in vitro and in vivo is mediated by the expression of SPI-6. We suggest that SPI-6 is an important endogenous mechanism to prevent rejection injury from perforin or granzyme B effectors and enhanced PI-9 or SPI-6 expressions by TEC may provide protection from diverse forms of inflammatory kidney injury and promote long-term allograft survival.

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