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.
Renal Transplant Unit, Academic Medical Center, Amsterdam, The Netherlands. T.Rowshani@AMC.UVA.NL
Ajda T
AT
Rowshani
Sandrine
S
Florquin
Frederike
F
Bemelman
J Alain
JA
Kummer
C Erik
CE
Hack
Ineke J M
IJ
Ten Berge
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