Serial peripheral blood interleukin-18 and perforin gene expression measurements for prediction of acute kidney graft rejection.
BACKGROUND
We and others have shown that expression of the cytotoxic T-lymphocyte effector gene perforin in the peripheral blood is a strong predictor of acute rejection in the early posttransplant period. In the present study we investigated whether interleukin (IL)-18, an immunostimulatory gene that up-regulates perforin-dependent cytotoxicity and promotes tissue damage through other noncytotoxic T-lymphocyte mechanisms alone or in combination with perforin gene expression, may serve as a better predictor of renal allograft rejection in the first weeks after transplantation.


METHODS
Peripheral blood was collected twice weekly, and gene expression was measured using real-time polymerase chain reaction.


RESULTS
Recipients with acute rejection (n = 17) showed higher levels of perforin and IL-18 transcript on days 5 to 7, 8 to 10, and 11 to 13, compared with patients without rejection (n = 37, P < 0.01 in all cases). Rejection diagnosis using gene expression criteria was possible 1 to 32 days before traditional diagnosis (median 11 days). High specificity was associated with IL-18 expression (72%-93%), and high sensitivity was associated with perforin expression (63%-90%). Positive predictive value was optimized (78%-100%) by using combined up-regulation in both genes as a diagnostic criterion (double-positive). Using high expression in "either or both" genes as a diagnostic criterion yielded high sensitivity (82%-91%) and negative predictive value (91%-96%).


CONCLUSIONS
Our data indicate that combined perforin and IL-18 gene expression measurements are useful tools for the recognition of graft rejection in its earliest stages. Serial measurements could be implemented as a monitoring system to identify patients at higher risk of rejection, making them candidates for biopsy or prophylactic increases in immunosuppression.
Simon
Tania
T
Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
Opelz
Gerhard
G
Wiesel
Manfred
M
Pelzl
Steffen
S
Ott
Ralf C
RC
Süsal
Caner
C
D000208:Acute Disease; D016022:Case-Control Studies; D015870:Gene Expression; D006084:Graft Rejection / Q000097:blood*; D006801:Humans; D020382:Interleukin-18 / Q000097:blood*; D016030:Kidney Transplantation; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011184:Postoperative Period; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000097:blood; D013997:Time Factors
D020382:Interleukin-18; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin