Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA.
Emory Transplant Center, Emory University, Atlanta, GA, USA.
Nat Biomed Eng. 2019 Apr;3(4):281-291. doi: 10.1038/s41551-019-0358-7. Epub 2019 Feb 18.
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.
早期发现移植排斥反应对于患者的长期存活至关重要。检测移植排斥反应的诊断金标准包括核心活检，该方法具有侵袭性，预测能力有限，且存在发病风险。在这里，我们证明了与肽底物偶联的纳米颗粒可以特异性地识别丝氨酸蛋白酶颗粒酶 B，颗粒酶 B 是受体 T 细胞在急性细胞排斥反应发作时产生的，可作为早期排斥反应的非侵入性生物标志物。当在皮肤移植物排斥反应的小鼠模型中系统给药时，这些纳米传感器优先在同种异体组织中积累，在同种异体组织中，它们被颗粒酶 B 切割，释放出可滤入受者尿液的荧光报告分子。随后，尿液分析可在移植物组织出现排斥反应特征之前，以高灵敏度和特异性来区分排斥反应的发生。此外，在接受亚治疗剂量免疫抑制药物治疗的小鼠中，在移植物失功之前就可以检测到尿液中的报告信号。该方法可能使我们无需进行活检即可常规监测移植物的状态。
