Acute allograft rejection in human liver transplant recipients is associated with signaling through toll-like receptor 4

作者：Testro Adam G^*; Visvanathan Kumar; Skinner Narelle; Markovska Vesna; Crowley Peter; Angus Peter W; Gow Paul J

来源：Journal of Gastroenterology and Hepatology, 2011, 26(1): 155-163.

DOI：10.1111/j.1440-1746.2010.06324.x

• damage associated molecular patterns
• inflammation
• innate immunity
• liver
• rejection

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-alpha (TNF-alpha) 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-alpha and IL-6 was also significantly increased. Post-transplant, the two groups differed with regard to TLR4-dependent TNF-alpha 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.

• 出版日期2011-1