Grandaliano G, Gesualdo L, Ranieri E, Monno R, Stallone G, Schena F P
Institute of Nephrology, University of Bari, Polyclinic, Italy.
Transplantation. 1997 Feb 15;63(3):414-20. doi: 10.1097/00007890-199702150-00015.
Mononuclear cell infiltration is a common histopathological feature of acute renal transplant rejection, in which it seems to play a key role in the pathogenesis of tubulointerstitial lesions. Monocyte chemotactic peptide-1 (MCP-1) is a specific chemotactic and activating factor for monocytes. Thus, the present study was aimed at evaluating MCP-1 gene and protein expression in renal biopsies of kidney transplant recipients with acute deterioration of graft function, and to correlate it with the extent of monocyte infiltration. We studied 20 kidney transplant recipients with acute graft dysfunction (13 with acute rejection, seven with acute tubular damage). MCP-1 gene and protein expression were analyzed by in situ hybridization and immunohistochemistry, respectively. CD68-positive cells were identified as monocytes. CD68-positive cell number and MCP-1 expression were quantified by a computerized image analysis system. MCP-1 gene expression, undetectable in normal human kidneys, was strikingly increased in patients with acute rejection. The chemokine localized mainly to the proximal tubular cells and to mononuclear-infiltrating cells. In patients with acute tubular damage, the MCP-1 expression, even if higher than in controls, was significantly lower than in acute rejection. The expression of the chemokine strictly correlated with the number of infiltrating monocytes (r=0.87, P<0.05). Moreover, we measured MCP-1 urinary excretion by ELISA, in eight normal subjects (36+/-16 pg/mg urine creatinine), in 13 clinically stable transplant recipients (33+/-9 pg/mg, ns vs. normal patients), in 12 transplant recipients with acute rejection (250+/-46 pg/mg, P<0.01 vs. normal patients), and in five transplant recipients with acute tubular damage (97+/-33 pg/mg, P<0.05 vs. controls and patients with acute rejection). Urinary MCP-1 excretion directly correlated with renal MCP-1 gene expression (r=0.65, P=0.05). Finally, we observed a significant reduction in MCP-1 urine levels in patients with acute rejection, who responded to the antirejection treatment. In conclusion, our data suggest that MCP-1 may play a critical role in modulating monocyte influx and consequent tubulointerstitial damage in acute rejection. Therefore, an increase in urinary MCP-1 excretion may represent an early signal of ongoing acute graft rejection.
单核细胞浸润是急性肾移植排斥反应常见的组织病理学特征，在肾小管间质病变的发病机制中似乎起着关键作用。单核细胞趋化蛋白-1（MCP-1）是一种针对单核细胞的特异性趋化和激活因子。因此，本研究旨在评估移植肾功能急性恶化的肾移植受者肾活检组织中MCP-1基因和蛋白的表达，并将其与单核细胞浸润程度相关联。我们研究了20例移植肾功能急性异常的肾移植受者（13例急性排斥反应，7例急性肾小管损伤）。分别通过原位杂交和免疫组织化学分析MCP-1基因和蛋白表达。将CD68阳性细胞鉴定为单核细胞。通过计算机图像分析系统对CD68阳性细胞数量和MCP-1表达进行定量。MCP-1基因表达在正常人类肾脏中无法检测到，在急性排斥反应患者中显著增加。趋化因子主要定位于近端肾小管细胞和单核浸润细胞。在急性肾小管损伤患者中，MCP-1表达虽高于对照组，但显著低于急性排斥反应患者。趋化因子的表达与浸润单核细胞数量密切相关（r = 0.87，P < 0.05）。此外，我们通过ELISA检测了8名正常受试者（尿肌酐中36±16 pg/mg）、13名临床稳定的移植受者（33±9 pg/mg，与正常患者无显著差异）、12名急性排斥反应的移植受者（250±46 pg/mg，与正常患者相比P < 0.01）以及5名急性肾小管损伤的移植受者（97±33 pg/mg，与对照组和急性排斥反应患者相比P < 0.05）的尿MCP-1排泄量。尿MCP-1排泄量与肾MCP-1基因表达直接相关（r = 0.65，P = 0.05）。最后，我们观察到对抗排斥治疗有反应的急性排斥反应患者尿MCP-1水平显著降低。总之，我们的数据表明MCP-1可能在调节急性排斥反应中单核细胞流入及随之而来的肾小管间质损伤中起关键作用。因此，尿MCP-1排泄增加可能是正在发生的急性移植排斥反应的早期信号。
