Methe Heiko, Zimmer Edgar, Grimm Cornelia, Nabauer Michael, Koglin Joerg
Department of Cardiology, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany.
Transplantation. 2004 Nov 15;78(9):1324-31. doi: 10.1097/01.tp.0000137930.40597.03.
Long-term success of cardiac transplantation is limited by various forms of graft rejection. The specific mechanisms initiating and controlling these highly specialized immune processes remain unclear so far.
To investigate the role of innate immunity in the development of allograft rejection, we assessed toll-like receptor (TLR)4 expression and typical downstream effects of TLR signaling (B7-1, interleukin [IL]-12, tumor necrosis factor [TNF]-alpha) in circulating CD14+ monocytes in 38 transplant recipients 1 to 3 years and in 10 transplant recipients 6 to 10 years after transplantation and compared them with 20 healthy controls using reverse transcription polymerase chain reaction, flow cytometry, and enzyme-linked immunoadsorbent assay. The results were matched with endothelial function testing as an early clinical indicator of transplant vasculopathy early after transplantation.
Allograft endothelial dysfunction (ED) was defined as a compromised coronary flow reserve (CFVR) to acetylcholine (CFVR<2 in 13 of 38 transplant recipients). In these patients, mRNA transcript levels for TLR4 (P<0.05) and surface expression of TLR4 (P<0.005) and B7-1 (P<0.05) on circulating monocytes as well as secretion of IL-12 (P<0.02) and TNF-alpha (P<0.05) were significantly higher than in the remaining 25 patients without ED. Compared with the controls, recipients late after transplantation did not show significantly elevated levels of TLR4 or dependent mediators. These results were compared with mRNA levels in a mice model of acute and chronic rejection. Rejecting mice exhibited elevated mRNA levels for mTLR4 and mB7-1.
Our results suggest activation of innate immunity in heart-transplant recipients through TLR4 contributes to the development of chronic rejection after cardiac transplantation.
心脏移植的长期成功受到各种形式的移植物排斥反应的限制。启动和控制这些高度专业化免疫过程的具体机制目前仍不清楚。
为了研究天然免疫在同种异体移植物排斥反应发生过程中的作用，我们采用逆转录聚合酶链反应、流式细胞术和酶联免疫吸附测定法，评估了38例移植后1至3年的受者及10例移植后6至10年的受者循环CD14+单核细胞中Toll样受体（TLR）4的表达以及TLR信号传导的典型下游效应（B7-1、白细胞介素[IL]-12、肿瘤坏死因子[TNF]-α），并将其与20名健康对照者进行比较。将结果与作为移植后早期移植血管病变早期临床指标的内皮功能测试结果相匹配。
同种异体移植物内皮功能障碍（ED）定义为对乙酰胆碱的冠状动脉血流储备（CFVR）受损（38例移植受者中有13例CFVR<2）。在这些患者中，循环单核细胞上TLR4的mRNA转录水平（P<0.05）、TLR4（P<0.005）和B7-1（P<0.05）的表面表达以及IL-12（P<0.02）和TNF-α（P<0.05）的分泌均显著高于其余25例无ED的患者。与对照组相比，移植后晚期受者的TLR4或相关介质水平未显著升高。将这些结果与急性和慢性排斥反应小鼠模型中的mRNA水平进行比较。发生排斥反应的小鼠mTLR4和mB7-1的mRNA水平升高。
我们的结果表明，通过TLR4激活心脏移植受者的天然免疫有助于心脏移植后慢性排斥反应的发生。
