Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
J Gastroenterol Hepatol. 2011 Jan;26(1):155-63. doi: 10.1111/j.1440-1746.2010.06324.x.
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.
Toll 样受体（TLR）信号转导是启动适应性免疫反应的关键步骤。TLR4 除了识别内毒素外，还识别内源性配体（“损伤相关结构”），这些配体在移植前期间释放到循环中。TLR2 在较小程度上也识别这些内源性配体。涉及实体器官移植的多项研究表明 TLR4 与同种异体移植物排斥之间存在明确的关联。在本研究中，我们评估了 TLR4 和 TLR2 依赖性反应与急性肝移植排斥之间是否存在关联。
该样本包括 26 名肝移植受者。在移植前和移植后 14 天的多个时间点采集血液。用 TLR4 和 TLR2 配体，即脂多糖和 Pam-3-Cys 分别刺激单核细胞。使用流式细胞术测定单核细胞 TLR 表达；酶联免疫吸附试验测定肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的产生。
9 例（34.6%）患者发生排斥。排斥组和非排斥组在年龄、性别、疾病或免疫抑制方面无差异。排斥组的基线 TLR4 表达明显更高（1.36 对 1.02，P=0.01）。TLR2 表达无差异。在排斥者中，基线 TLR4 和 TLR2 依赖性 TNF-α和 IL-6 的产生也显著增加。移植后，两组在 TLR4 依赖性 TNF-α产生方面存在差异，排斥者在第一周内逐渐下调。
在肝移植前，随后发生排斥的患者表现出强烈的 TLR4 依赖性免疫反应，而不发生排斥的患者则没有。这支持了损伤相关结构通过 TLR4 信号转导可能负责早期激活同种异体 T 细胞，有利于移植物排斥的理论。
