Applied Immunobiology and Transplantation Research Group, Insitute of Cellular Medicine, Newcastle University, United Kingdom.
Transplantation. 2010 Jun 15;89(11):1411-6. doi: 10.1097/TP.0b013e3181da604b.
Inflammatory cell recruitment during allograft rejection is driven by a group of inflammatory cytokines termed chemokines. Chemokines are presented on the surface of the vascular endothelium where they ligate specific receptors expressed on the surface of leukocytes. Recently, a group of nonsignaling chemokine receptors have been described. These bind and internalize chemokines but do not drive leukocyte migration. It is believed that these compete with classical signaling receptors to modulate inflammation.
This study describes the first examination of the human decoy chemokine receptor D6 during rejection; D6 binds at least 12 potent proinflammatory chemokines. The expression of D6 by graft infiltrating leukocytes was examined in cardiac allografts by confocal microscopy on biopsy sections (n=19). Cytokine regulation of D6 was examined in vitro, and a chemokine scavenging assay was performed using the prototypical transplant-associated chemokine CCL5/RANTES.
D6 expression was found to be higher in the biopsies taken from more severe cardiac allograft rejection (P<0.01) and was predominantly localized to graft infiltrating CD45(+)CD68(+) leukocytes. In vitro studies demonstrated that the transforming growth factor-beta strongly increased the expression of D6 by monocytes, which significantly enhanced D6-mediated chemokine scavenging (by 85%, P<0.05).
We present the first examination of the biology of D6 during rejection and identify a transplant-associated cytokine that is able to regulate its expression. These data suggest an exciting new mechanism for the antiinflammatory actions of transforming growth factor-beta. Understanding the expression patterns of D6 may provide important insight into the regulation and control of inflammatory cell recruitment during allograft rejection.
同种异体移植排斥过程中的炎症细胞募集是由一组被称为趋化因子的炎症细胞因子驱动的。趋化因子在血管内皮细胞表面表达，与白细胞表面表达的特定受体结合。最近，一组非信号转导趋化因子受体已被描述。这些受体结合并内化趋化因子，但不驱动白细胞迁移。据信，这些受体与经典信号转导受体竞争以调节炎症。
本研究首次描述了人类诱饵趋化因子受体 D6 在排斥反应中的作用；D6 至少结合 12 种有效的促炎趋化因子。通过共聚焦显微镜在活检切片上检查心脏移植中浸润的白细胞中的 D6 表达（n=19）。在体外检查了 D6 的细胞因子调节，并使用典型的移植相关趋化因子 CCL5/RANTES 进行了趋化因子清除测定。
发现 D6 的表达在取自更严重的心脏同种异体移植排斥的活检中更高（P<0.01），并且主要定位于浸润的 CD45(+)CD68(+)白细胞。体外研究表明，转化生长因子-β强烈增加单核细胞中 D6 的表达，这显著增强了 D6 介导的趋化因子清除（增加 85%，P<0.05）。
我们首次研究了 D6 在排斥反应过程中的生物学，并确定了一种与移植相关的细胞因子，能够调节其表达。这些数据表明转化生长因子-β的抗炎作用具有令人兴奋的新机制。了解 D6 的表达模式可能为了解同种异体移植排斥过程中炎症细胞募集的调节和控制提供重要的见解。
