Background and Aims:  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.

Methods:  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.

Results:  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.

Conclusions:  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.