Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Mol Immunol. 2010 Feb;47(5):1047-57. doi: 10.1016/j.molimm.2009.11.012. Epub 2009 Dec 11.
Acute renal allograft damage is caused by early leukocyte infiltration which is mediated in part by chemokines presented by glycosaminoglycan (GAG) structures on endothelial surfaces. CXCL8 can recruit neutrophils and induce the firm arrest of monocytes on activated endothelial cells. A human CXCL8-based antagonist (dnCXCL8) designed to generate a dominant-negative mutant protein with enhanced binding to GAG structures and reduced CXCR1/2 receptor binding ability was tested in models of early allograft injury. The agent displayed enhanced binding to GAG structures in vitro and could antagonize CXCL8-induced firm adhesion of monocytes as well as neutrophils to activated microvascular endothelium in physiologic flow assays. In a rat model of acute renal damage, dnCXCL8 treatment limited proximal tubular damage and reduced granulocyte infiltration. In a Fischer 344 (RT1(lvl)) to Lewis (RT1(l)) rat acute renal allograft model, dnCXCL8 was found to reduce monocyte and CD8+ T-cell infiltration into glomeruli and to limit tubular interstitial inflammation and tubulitis in vivo. Early treatment of allografts with agents like dnCXCL8 may help reduce acute allograft damage and preserve renal morphology and thereby help limit chronic dysfunction.
急性肾移植损伤是由早期白细胞浸润引起的，部分是由内皮表面糖胺聚糖 (GAG) 结构呈现的趋化因子介导的。CXCL8 可以募集中性粒细胞，并诱导单核细胞在激活的内皮细胞上牢固地停滞。一种基于人 CXCL8 的拮抗剂 (dnCXCL8) 旨在产生一种具有增强与 GAG 结构结合能力和降低 CXCR1/2 受体结合能力的显性负突变蛋白，在早期移植物损伤模型中进行了测试。该药物在体外显示出与 GAG 结构的增强结合，并能够拮抗 CXCL8 诱导的单核细胞和中性粒细胞在生理流动测定中与激活的微血管内皮牢固粘附。在急性肾损伤大鼠模型中，dnCXCL8 治疗可限制近端肾小管损伤并减少粒细胞浸润。在 Fischer 344（RT1(lvl)) 到 Lewis (RT1(l)) 大鼠急性肾移植模型中，dnCXCL8 被发现可减少单核细胞和 CD8+T 细胞浸润到肾小球，并在体内限制肾小管间质炎症和肾小管炎。早期用 dnCXCL8 等药物处理移植物可能有助于减少急性移植物损伤并保持肾脏形态，从而有助于限制慢性功能障碍。
