Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Bioinformatics Research Group, University of Applied Sciences Upper Austria, Softwarepark 13, 4232, Hagenberg im Muehlkreis, Austria.
BMC Nephrol. 2019 Sep 2;20(1):346. doi: 10.1186/s12882-019-1541-5.
Kidney transplantation is the optimal treatment in end stage renal disease but the allograft survival is still hampered by immune reactions against the allograft. This process is driven by the recognition of allogenic antigens presented to T-cells and their unique T-cell receptor (TCR) via the major histocompatibility complex (MHC), which triggers a complex immune response potentially leading to graft injury. Although the immune system and kidney transplantation have been studied extensively, the subtlety of alloreactive immune responses has impeded sensitive detection at an early stage. Next generation sequencing of the TCR enables us to monitor alloreactive T-cell populations and might thus allow the detection of early rejection events.
METHODS/DESIGN: This is a prospective cohort study designed to sequentially evaluate the alloreactive T cell repertoire after kidney transplantation. The TCR repertoire of patients who developed biopsy confirmed acute T cell mediated rejection (TCMR) will be compared to patients without rejection. To track the alloreactive subsets we will perform a mixed lymphocyte reaction between kidney donor and recipient before transplantation and define the alloreactive TCR repertoire by next generation sequencing of the complementary determining region 3 (CDR3) of the T cell receptor beta chain. After initial clonotype assembly from sequencing reads, TCR repertoire diversity and clonal expansion of T cells of kidney transplant recipients in periphery and kidney biopsy will be analyzed for changes after transplantation, during, prior or after a rejection. The goal of this study is to describe changes of overall T cell repertoire diversity, clonality in kidney transplant recipients, define and track alloreactive T cells in the posttransplant course and decipher patterns of expanded alloreactive T cells in acute cellular rejection to find an alternative monitoring to invasive and delayed diagnostic procedures.
Changes of the T cell repertoire and tracking of alloreactive T cell clones after combined bone marrow and kidney transplant has proven to be of potential use to monitor the donor directed alloresponse. The dynamics of the donor specific T cells in regular kidney transplant recipients in rejection still rests elusive and can give further insights in human alloresponse.
Clinicaltrials.gov: NCT03422224 , registered February 5th 2018.
肾移植是终末期肾病的最佳治疗方法，但同种异体移植物的存活率仍然受到针对移植物的免疫反应的阻碍。这个过程是由 T 细胞识别同种异体抗原和它们独特的 T 细胞受体（TCR）驱动的，这些抗原和 TCR 通过主要组织相容性复合体（MHC）呈现，从而引发潜在导致移植物损伤的复杂免疫反应。尽管免疫系统和肾移植已经得到了广泛的研究，但同种反应性免疫反应的微妙之处阻碍了早期的敏感检测。TCR 的下一代测序使我们能够监测同种反应性 T 细胞群体，从而可能检测到早期排斥事件。
方法/设计：这是一项前瞻性队列研究，旨在连续评估肾移植后同种反应性 T 细胞库。将比较发生活检证实的急性 T 细胞介导排斥反应（TCMR）的患者与无排斥反应的患者的 TCR 库。为了跟踪同种反应性亚群，我们将在移植前进行肾供体和受者之间的混合淋巴细胞反应，并通过下一代测序确定 T 细胞受体β链的互补决定区 3（CDR3）的同种反应性 TCR 库。从测序读数初始组装克隆型后，将分析肾移植受者外周血和肾活检中 T 细胞的 TCR 库多样性和克隆扩增，以在移植后、排斥前或排斥后分析移植后的变化。本研究的目的是描述整体 T 细胞库多样性、肾移植受者克隆性的变化，定义并跟踪移植后的同种反应性 T 细胞，并解析急性细胞性排斥中扩展的同种反应性 T 细胞的模式，以找到替代侵袭性和延迟诊断程序的监测方法。
骨髓和肾联合移植后 T 细胞库的变化和同种反应性 T 细胞克隆的跟踪已被证明对监测供体定向同种反应具有潜在用途。在排斥反应的常规肾移植受者中，供体特异性 T 细胞的动力学仍然难以捉摸，可以进一步了解人类同种反应。
Clinicaltrials.gov：NCT03422224，于 2018 年 2 月 5 日注册。
