Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

中文翻译：

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肾上腺皮质激素1参与慢性同种异体移植排斥反应的发展。

慢性同种异体移植排斥是长期同种异体移植失败的最常见原因。原因之一是目前用于慢性同种异体移植排斥反应的诊断和治疗方法非常有限。我们在这里显示肾脏移植物中增强的NFκB信号促成慢性活性抗体介导的排斥反应（CAAMR），这是慢性肾脏同种异体移植排斥反应的主要病理。此外，我们发现尿类类固醇1（ORM1）是CAAMR的候选标记分子和治疗靶标。实际上，经病理诊断为CAAMR的肾移植接受者的尿中ORM1浓度明显高于组织学正常，钙调神经磷酸酶抑制剂毒性或间质纤维化和肾小管萎缩的肾移植接受者。另外，我们发现，与非CAAMR样品相比，具有CAAMR的肾脏活检样品在肾小管细胞中表达的ORM1更高，并具有更高的NFκB和STAT3活化。一致地，在原代肾小管细胞中细胞因子介导的NFκB和STAT3激活后，诱导ORM1产生。ORM1的功能丧失和功能获得分别抑制和促进NFκB活化。最后，ORM1增强了NFκB介导的体内炎症发展。这些结果表明，肾移植后慢性同种异体移植排斥反应的发生与移植物中NFκB和STAT3激活后增强的NFκB依赖性途径有关，ORM1是一种非侵入性候选生物标志物，并且可能是慢性肾脏同种异体移植排斥反应的治疗靶标。