Transforming growth factor-beta and matrix protein expression in acute and chronic rejection of human renal allografts.
Because the increased tissue expression of TGF-beta underlies fibrosis in many diseases, it was hypothesized that sustained elevated transforming growth factor (TGF)-beta overexpression might be responsible for fibrosis in chronic rejection of the renal allograft. To test this hypothesis, biopsies were obtained from 5 patients with acute rejection, 5 patients with chronic rejection, 10 normal individuals, and 10 patients with kidney disease. The tissues were examined by immunofluorescence for the three TGF-beta isoforms (1, 2, and 3) and the two matrix proteins induced by TGF-beta that serve as markers of fibrosis: fibronectin extradomain A positive (EDA+) and plasminogen activator inhibitor-1 (PAI-1). The tubulointerstitium from all cases of acute rejection and chronic rejection showed highly significant increases in immunostaining for the three TGF-beta isoforms (P < 0.001), fibronectin EDA+ (P < 0.005), and PAI-1 (P < 0.001). In the glomeruli, only TGF-beta 1 expression achieved statistical significance (P < 0.005) in acute rejection, whereas in chronic rejection, all three TGF-beta isoforms (p < 0.001) in addition to fibronectin EDA+ (p < 0.001) and PAI-1 (p < 0.001) were elevated. There was both cellular and matrix staining of the TGF-beta isoforms. In striking contrast, control kidney tissues were negative or only weakly positive. Because TGF-beta was present both in acute and in chronic rejection but not in control tissues and because acute rejection episodes are a good predictor for chronic rejection, these results suggest that TGF-beta may play a role in the pathogenesis of fibrosis in chronic rejection.
Shihab
F S
FS
Division of Nephrology, University of Utah School of Medicine, Salt Lake City 84132, USA.
Yamamoto
T
T
Nast
C C
CC
Cohen
A H
AH
Noble
N A
NA
Gold
L I
LI
Border
W A
WA
D000208:Acute Disease; D002908:Chronic Disease; D005353:Fibronectins / Q000096:biosynthesis*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta