Hyperexpression of the granzyme B inhibitor PI-9 in human renal allografts: a potential mechanism for stable renal function in patients with subclinical rejection.
BACKGROUND
Granzyme B-positive T lymphocytes infiltrate renal allografts during acute cellular rejection and cause graft injury by inducing apoptosis of tubular cells. Protease inhibitor 9 (PI-9), an intracellular serpin that inhibits granzyme B, is known to protect cells from the action of cytotoxic T lymphocytes.


METHODS
Expression of granzyme B and PI-9 in transplant biopsies from patients with acute cellular rejection (N= 18), subclinical rejection showing a mononuclear cell infiltrate without deterioration of renal function (N= 15), or stable transplant function (N= 13) were studied. Immunohistochemical stainings were analyzed and scored semiquantitatively by two independent observers who were not aware of clinical results.


RESULTS
Granzyme B was expressed by mononuclear cells in all biopsies with cellular infiltrates. PI-9 was diffusely expressed by tubular cells in the allografts of all patients with subclinical rejection. In contrast, PI-9 expression was only focally in the patients with clinical rejection or without rejection. Although no difference was observed in granzyme B levels between acute and subclinical rejection, in subclinical rejection tubular epithelial cells showed significantly stronger expression of PI-9 than in acute rejection (P= 0.011).


CONCLUSIONS
These data suggest that a high expression of PI-9 by tubular epithelial cells can serve as one of the factors protecting renal allografts from rejection in spite of the presence of inflammatory cell infiltrates.
Rowshani
Ajda T
AT
Renal Transplant Unit, Academic Medical Center, Amsterdam, The Netherlands. T.Rowshani@AMC.UVA.NL
Florquin
Sandrine
S
Bemelman
Frederike
F
Kummer
J Alain
JA
Hack
C Erik
CE
Ten Berge
Ineke J M
IJ
D000208:Acute Disease; D002908:Chronic Disease; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D053804:Granzymes; D006801:Humans; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D008214:Lymphocytes / Q000201:enzymology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D014184:Transplantation, Homologous
C102316:SERPINB9 protein, human; D015843:Serpins; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases