Intragraft Toll-like receptor profiling in acute renal allograft rejection.
BACKGROUND
Experimental studies have shown potential for Toll-like receptor (TLR) profiling in renal allograft in predicting renal outcome after transplantation. Our goal was to determine if profiling of TLR1-10 and TLR-related genes could be used as a prognostic value for renal function and late clinical outcome after transplantation.


METHODS
TLR1-10, CD14, MD-2 and negative regulators Toll-interacting protein (TOLLIP) and single immunoglobulin domain IL-1R-related receptor were analysed in 36 biopsies from renal transplant recipients with acute rejection (AR) and in 14 biopsies from renal transplant recipients without rejection (NR). Analysis was performed by multiplex ligation-dependent probe amplification. TLR (-related) genes were correlated to Banff'07 classification, cellular influx, response to conventional anti-rejection therapy, renal function 12 and 24 months after rejection and graft loss.


RESULTS
mRNA levels of most TLRs were significantly higher in acute rejection while TOLLIP mRNA level was decreased. mRNA levels of TLR1/2/4/7/8 were highly accurate in distinguishing AR from NR. TLR mRNA levels correlated to inflammatory parameters according to the Banff'07 classification and to cellular influx. Elevated mRNA level of TLR3 in acute rejection was independent from infiltrating leukocytes. TLR (-related) genes were not correlated with response to conventional anti-rejection therapy. Splice variant TLR4r3 was associated with poor renal function 24 months after transplantation, and TLR1 appeared to be associated with graft loss.


CONCLUSIONS
The elevated mRNA levels of several TLRs in association with reduced mRNA levels of TOLLIP in renal transplant biopsies of patients with acute rejection indicate a pro-inflammatory state, which may contribute to uncontrolled inflammation.
Dessing
Mark C
MC
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.c.dessing@amc.uva.nl
Bemelman
Frederike J
FJ
Claessen
Nike
N
Ten Berge
Ineke J M
IJ
Florquin
Sandrine
S
Leemans
Jaklien C
JC
D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C495377:LY96 protein, human; C546891:SIGIRR protein, human; C410602:TOLLIP protein, human