Lan H Y, Yang N, Brown F G, Isbel N M, Nikolic-Paterson D J, Mu W, Metz C N, Bacher M, Atkins R C, Bucala R
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Transplantation. 1998 Dec 15;66(11):1465-71. doi: 10.1097/00007890-199812150-00009.
Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown.
MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney.
MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection.
This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.
巨噬细胞移动抑制因子（MIF）在免疫介导的疾病中起关键作用。尽管MIF与迟发型超敏反应长期相关，但MIF在同种异体移植排斥中的潜在作用尚不清楚。
通过原位杂交和免疫组织化学染色评估62例人类肾移植排斥活检组织和正常人类肾脏中MIF的表达。
MIF mRNA和蛋白在正常肾脏中组成性表达，主要局限于肾小管上皮细胞、一些肾小球上皮细胞和血管平滑肌细胞。在急性和慢性肾移植排斥中，肾小管上皮细胞、血管内皮细胞和平滑肌细胞等固有肾细胞的MIF mRNA和蛋白表达均显著上调。浸润的巨噬细胞和T细胞也有MIF表达。值得注意的是，巨噬细胞和T细胞浸润主要局限于MIF表达显著上调的区域，可能导致严重肾小管炎和内膜或透壁性动脉炎的发生。定量分析发现，移植排斥中MIF表达增加与肾小球和间质中巨噬细胞和T细胞积聚高度相关（P<0.001）。此外，MIF+肾小管数量和间质MIF+细胞数量与移植排斥严重程度显著相关（P<0.01），与肾功能丧失也显著相关（P<0.01）。相比之下，在无排斥证据的移植活检组织中未观察到肾MIF表达上调和白细胞积聚。
这是第一项证明同种异体移植排斥期间局部MIF表达上调的研究。MIF表达上调、巨噬细胞和T细胞浸润与肾移植排斥严重程度之间的关联表明，MIF可能是同种异体移植排斥过程中的重要介质。
