Savikko Johanna, Kallio Erkki A, Taskinen Eero, von Willebrand Eva
Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Finland.
Transplantation. 2002 Feb 27;73(4):506-11. doi: 10.1097/00007890-200202270-00003.
In the development of chronic kidney allograft rejection acute rejection (AR) is the single most important risk factor. Although Cyclosporin A (CsA) medication has decreased the incidence of AR, chronic rejection (CR) is still the major reason for late allograft loss. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CR. We have investigated the impact of AR and different doses of CsA on the expression of PDGF ligands and receptors in the development of CR.
Kidney transplantations were performed from DA to WF rats and syngenic controls were done from DA to DA rats. Two groups of allografts were treated daily with CsA either at low dose (1.5 mg/kg) or high dose (5 mg/kg). Third group of allografts was treated with CsA 5 mg/kg/day for 1 week and then left untreated until the development of AR. AR episodes were treated with CsA 5 mg/kg/day. Grafts were harvested 3 months after transplantation for histology and immunohistochemistry (PDGF-AA, -BB and PDGFR-alpha, -beta).
In syngenic grafts no histological signs of CR were seen and the expression of PDGF ligands and receptors remained almost nonexistent. AR episodes increased the chronic rejection changes. High-dose CsA-treatment ameliorated inflammation compared to low-dose CsA-treatment, although it failed to inhibit the development of chronic changes. More fibrosis was even seen in high-dose than in low-dose CsA-treated grafts. CR in each allograft group was associated with induction of all PDGF ligands and receptors (P<0.05 compared with syngenic controls) in interstitial inflammatory cells, capillary endothelium, and arterial smooth muscle cells. In the group with AR episodes the expression was further increased.
Our results demonstrate that CsA treatment cannot inhibit the expression of PDGF ligands and receptors in the development of chronic kidney allograft rejection and that AR episodes induce even more PDGF and its receptors in the graft indicating a link between AR and subsequent development of CR.
在慢性肾移植排斥反应的发展过程中，急性排斥反应（AR）是唯一最重要的危险因素。尽管环孢素A（CsA）药物治疗降低了AR的发生率，但慢性排斥反应（CR）仍是移植肾晚期丢失的主要原因。血小板衍生生长因子（PDGF）是介导CR中间充质细胞增殖的主要促有丝分裂原。我们研究了AR和不同剂量的CsA对CR发展过程中PDGF配体和受体表达的影响。
将DA大鼠的肾脏移植到WF大鼠体内，并将DA大鼠之间的同基因对照移植作为对照。两组同种异体移植肾每天分别接受低剂量（1.5mg/kg）或高剂量（5mg/kg）的CsA治疗。第三组同种异体移植肾先接受5mg/kg/天的CsA治疗1周，然后不再治疗直至发生AR。AR发作时用5mg/kg/天的CsA治疗。移植后3个月采集移植物进行组织学和免疫组织化学检查（检测PDGF-AA、-BB以及PDGFR-α、-β）。
在同基因移植物中未观察到CR的组织学迹象，PDGF配体和受体的表达几乎不存在。AR发作增加了慢性排斥反应的改变。与低剂量CsA治疗相比，高剂量CsA治疗减轻了炎症，尽管它未能抑制慢性改变的发展。高剂量CsA治疗的移植物中甚至比低剂量CsA治疗的移植物有更多的纤维化。每个同种异体移植肾组的CR均与间质炎性细胞、毛细血管内皮细胞和动脉平滑肌细胞中所有PDGF配体和受体的诱导表达有关（与同基因对照相比，P<0.05）。在发生AR发作的组中，表达进一步增加。
我们的结果表明，CsA治疗不能抑制慢性肾移植排斥反应发展过程中PDGF配体和受体的表达，并且AR发作会在移植物中诱导更多的PDGF及其受体表达，这表明AR与随后的CR发展之间存在联系。
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