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Title: Acute allograft rejection in human liver transplant recipients is associated with signaling through toll-like receptor 4.
Austin Authors: Testro, Adam G ;Visvanathan, Kumar;Skinner, Narelle;Markovska, Vesna;Crowley, Peter;Angus, Peter W ;Gow, Paul J 
Affiliation: General Medicine
Issue Date: 1-Jan-2011
Publication information: Journal of Gastroenterology and Hepatology; 26(1): 155-63
Abstract: Toll-like receptor (TLR) signaling is a crucial step in initiating adaptive immune responses. In addition to recognizing endotoxin, TLR4 also recognizes endogenous ligands ('damage-associated structures'), which are released into the circulation in the peri-transplantation period. TLR2 to a lesser extent also recognizes these endogenous ligands. Multiple studies involving solid organ transplants demonstrate a clear association between TLR4 and allograft rejection. In the present study we assessed whether an association exists between TLR4 and TLR2-dependent responses and acute liver allograft rejection.The sample included 26 liver transplant recipients. Blood was taken pre-transplant and at multiple points over the first 14 days post-transplant. Monocytes were stimulated with TLR4 and TLR2 ligands, lipopolysaccharide and Pam-3-Cys, respectively. Monocyte TLR expression was determined using flow cytometry; enzyme-linked immunosorbent assays measured tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production.Nine (34.6%) patients experienced rejection. No differences existed in age, sex, disease or immunosuppression between rejectors and non-rejectors. Baseline TLR4 expression was significantly higher in rejectors (1.36 vs 1.02, P=0.01). There was no difference in TLR2 expression. In rejectors, baseline TLR4- and TLR2-dependent production of TNF-α and IL-6 was also significantly increased. Post-transplant, the two groups differed with regard to TLR4-dependent TNF-α production, with rejectors demonstrating progressive downregulation over the first week.Prior to liver transplantation, patients who subsequently experience rejection demonstrate robust TLR4-dependent immune responses, which are not seen in those who do not reject. This supports the theory that damage-associated structures signaling through TLR4 may be responsible for the early activation of alloimmune T-cells, favoring allograft rejection.
DOI: 10.1111/j.1440-1746.2010.06324.x
Journal: Journal of Gastroenterology and Hepatology
Type: Journal Article
Subjects: Acute Disease
Antigens, CD14.metabolism
Cells, Cultured
Cysteine.analogs & derivatives.pharmacology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Graft Rejection.immunology
Immunity, Innate.drug effects
Liver Transplantation.immunology
Middle Aged
Monocytes.drug effects.immunology
Pilot Projects
Prospective Studies
Signal Transduction.drug effects
Time Factors
Toll-Like Receptor 2.agonists.metabolism
Toll-Like Receptor 4.agonists.metabolism
Transplantation, Homologous
Tumor Necrosis Factor-alpha.metabolism
Appears in Collections:Journal articles

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