Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation.
BACKGROUND
Although innate immunity is crucial to host defense against pathogens, the extent to which innate immune mechanisms participate in the rejection of allogenic tissues in humans is unknown. We hypothesize that activation of innate immunity through Toll-like receptors (TLRs) critically regulates the development of renal allograft rejection. We have recently demonstrated decreased acute rejection in lung transplant recipients heterozygous for either of two functional polymorphisms in TLR4 associated with endotoxin hyporesponsiveness. In the present investigation, we sought to evaluate the role of innate immune activation through TLR4, in either donor or recipient, upon the development of renal allograft rejection.


METHODS
Patients and donors were screened for the TLR4 functional polymorphisms (Asp299Gly and Thr399Ile) by polymerase chain reaction (PCR) using sequence-specific primers.


RESULTS
The incidence of biopsy-proven acute renal allograft rejection was significantly reduced in patients receiving donor grafts heterozygous for the Asp299Gly or Thr399Ile alleles, when compared with wild type (22% vs. 0%, respectively, p = 0.02). There was no association with recipient TLR4 allele and rejection.


CONCLUSIONS
The results suggest activation of innate immunity through TLR4 in the donor kidney contributes to the development of acute rejection after renal transplantation.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. palme002@mc.duke.edu
Scott M
SM
Palmer
Lauranell H
LH
Burch
Saad
S
Mir
Stephen R
SR
Smith
Paul C
PC
Kuo
Walter F
WF
Herczyk
Nancy L
NL
Reinsmoen
David A
DA
Schwartz
D000328:Adult; D001424:Bacterial Infections / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology / Q000502:physiology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011183:Postoperative Complications / Q000453:epidemiology; D051197:Toll-Like Receptor 4 / Q000235:genetics*
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4