CD47 blockade reduces ischemia-reperfusion injury and improves outcomes in a rat kidney transplant model.
CD47 blockade reduces ischemia-reperfusion injury and improves outcomes in a rat kidney transplant model.
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DOI：
10.1097/tp.0000000000000252
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发表时间：
2014-08-27
期刊：
影响因子：
6.2
通讯作者：
Chapman WC
中科院分区：
文献类型：
--
作者：
Lin Y;Manning PT;Jia J;Gaut JP;Xiao Z;Capoccia BJ;Chen CC;Hiebsch RR;Upadhya G;Mohanakumar T;Frazier WA;Chapman WC
缺血/再灌注损伤（IRI）显著地导致移植物功能延迟和炎症，从而导致移植物损失。血小板反应蛋白-1/CD47系统通过抑制一氧化氮信号传导加剧IRI。我们推测，阻断CD 47和预防一氧化氮抑制可降低器官移植中的IRI。我们采用同基因大鼠肾移植模型，双侧肾切除受体IRI的评估的影响，CD 47单克隆抗体（CD 47单克隆抗体）对IRI。供体肾用CD 47 mAb OX 101或同种型匹配的对照免疫球蛋白冲洗，并在移植前在4°C下在UW溶液中储存6小时。CD 47单抗灌注供体肾可显著改善移植后存活率，降低血清肌酐、BUN、磷和镁水平，减少损伤的组织学证据。相反，对照组存活不超过5天，肾损伤的生化指标增加，并表现出严重的病理损伤，肾小管萎缩和坏死。与对照组相比，接受CD 47 mAb治疗的肾脏显示肾损伤的血浆生物标志物水平降低，包括胱抑素C、骨桥蛋白、TIMP 1、β2-微球蛋白、VEGF-A和丛生蛋白。此外，激光多普勒评估显示在CD 47 mAb处理的肾脏中肾血流量更高。这些结果为使用CD 47抗体介导的阻断来减少IRI和改善肾移植的器官保存提供了强有力的证据。
Ischemia/reperfusion injury (IRI) significantly contributes to delayed graft function and inflammation leading to graft loss. IRI is exacerbated by the thrombospondin-1/CD47 system through inhibition of nitric oxide signaling. We postulate that CD47 blockade and prevention of nitric oxide inhibition reduces IRI in organ transplantation. We used a syngeneic rat renal transplantation model of IRI with bilaterally nephrectomized recipients to evaluate the effect of a CD47 monoclonal antibody (CD47mAb) on IRI. Donor kidneys were flushed with CD47mAb OX101 or an isotype-matched control immunoglobulin and stored at 4°C in UW solution for 6 hours prior to transplantation. CD47mAb perfusion of donor kidneys resulted in marked improvement in post-transplant survival, lower levels of serum creatinine, BUN, phosphorus and magnesium and less histologic evidence of injury. In contrast, control groups did not survive more than 5 days, had increased biochemical indicators of renal injury and exhibited severe pathological injury with tubular atrophy and necrosis. Recipients of CD47mAb-treated kidneys showed decreased levels of plasma biomarkers of renal injury including cystatin C, osteopontin, TIMP1, β2-microglobulin, VEGF-A and clusterin compared to the control group. Furthermore, laser Doppler assessment showed higher renal blood flow in the CD47mAb-treated kidneys. These results provide strong evidence for the use of CD47 antibody-mediated blockade to reduce IRI and improve organ preservation for renal transplantation.