Non-invasive early detection of acute transplant rejection via nanosensors of granzyme B activity
Non-invasive early detection of acute transplant rejection via nanosensors of granzyme B activity
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DOI：
10.1038/s41551-019-0358-7
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发表时间：
2019-04-01
影响因子：
28.1
通讯作者：
Kwong, Gabriel A.
中科院分区：
文献类型：
--
作者：
Mac, Quoc D.;Mathews, Dave, V;Kwong, Gabriel A.
早期发现移植排斥反应对于患者的长期生存至关重要。检测移植排斥的诊断金标准涉及核心活检，这是侵入性的，预测能力有限，并且存在发病风险。在这里，我们证明，与丝氨酸蛋白酶颗粒酶 B 特异性的肽底物缀合的纳米颗粒可以作为早期排斥的非侵入性生物标志物，丝氨酸蛋白酶颗粒酶 B 是由受体 T 细胞在急性细胞排斥反应发生期间产生的。当在皮肤移植排斥反应的小鼠模型中全身给药时，这些纳米传感器优先积聚在同种异体移植组织中，在那里它们被颗粒酶 B 裂解，释放出荧光报告基因，过滤到受体的尿液中。然后，在移植组织中出现明显的排斥反应之前，尿液分析可以以高灵敏度和特异性辨别排斥反应的发生。此外，在接受亚治疗水平的免疫抑制药物治疗的小鼠中，可以在移植失败之前检测到尿液中的报告信号。该方法可以实现同种异体移植物状态的常规监测，而无需活检。
The early detection of the onset of transplant rejection is critical for the long-term survival of patients. The diagnostic gold standard for detecting transplant rejection involves a core biopsy, which is invasive, has limited predictive power and carries a morbidity risk. Here, we show that nanoparticles conjugated with a peptide substrate specific for the serine protease granzyme B, which is produced by recipient T cells during the onset of acute cellular rejection, can serve as a non-invasive biomarker of early rejection. When administered systemically in mouse models of skin graft rejection, these nanosensors preferentially accumulate in allograft tissue, where they are cleaved by granzyme B, releasing a fluorescent reporter that filters into the recipient's urine. Urinalysis then discriminates the onset of rejection with high sensitivity and specificity before features of rejection are apparent in grafted tissues. Moreover, in mice treated with subtherapeutic levels of immunosuppressive drugs, the reporter signals in urine can be detected before graft failure. This method may enable routine monitoring of allograft status without the need for biopsies.