T Cell Clonal Dynamics Determined by High-Resolution TCR-β Sequencing in Recipients after Allogeneic Hematopoietic Cell Transplantation.
T Cell Clonal Dynamics Determined by High-Resolution TCR-β Sequencing in Recipients after Allogeneic Hematopoietic Cell Transplantation.
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DOI：
10.1016/j.bbmt.2020.04.026
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Chen YB
中科院分区：
文献类型：
--
作者：
Leick M;Gittelman RM;Yusko E;Sanders C;Robins H;DeFilipp Z;Nikiforow S;Ritz J;Chen YB
免疫系统重建延迟是异基因造血细胞移植（HCT）后长期公认的并发症。具体而言，T细胞多样性的丧失被认为有助于感染性并发症、移植物抗宿主病（GVHD）和疾病复发。我们在HCT后的前3个月期间使用immunoSEQ® Assay对99名相关或不相关供体（51名不相关，39名相关）HCT（55名降低强度预处理，44名清髓性预处理）接受者进行了TCR-β的连续高分辨率下一代测序。我们在多个时间点测量了来自受体样品的T细胞分数、克隆性（1- Peilou均匀度）和Daley-Smith丰富度。与先前的研究一致，我们发现，尽管绝对T细胞数量在移植后恢复相对较快，但T细胞库的多样性仍然减少。有限的多样性与条件反射强度、ATG的使用和供体类型相关。与供体T细胞克隆相比，在第+30天时扩增克隆数量的增加与急性GVHD的发生率相关（HR=1.11，p= 5x 10 −5）。即使排除了在第+30天之前发生急性GVHD的12名患者，在第+30天急性GVHD和增加的克隆扩增之间的关联仍然存在（HR=1.098，p=0.041），表明增加的克隆T细胞扩增先于急性GVHD的发生。我们的研究结果强调了T细胞克隆扩增作为急性GVHD潜在的新生物标志物，值得进一步研究。
Delayed reconstitution of the immune system is a long-recognized complication after allogeneic hematopoietic cell transplantation (HCT). Specifically, loss of T-cell diversity has been thought to contribute to infectious complications, graft versus host disease (GVHD) and disease relapse. We performed serial high-resolution next generation sequencing of TCR-β in 99 related or unrelated donor (51 unrelated, 39 related) HCT (55 reduced intensity conditioning, 44 myeloablative conditioning) recipients during the first 3 months after HCT using the immunoSEQ® Assay. We measured T-cell fraction, clonality (1- Peilou’s eveness) and Daley-Smith richness from recipient samples at multiple time points. In agreement with prior studies, we found that although absolute T-cell numbers recover relatively quickly after transplant, T-cell repertoire diversity remains diminished. Restricted diversity was associated with conditioning intensity, use of ATG, and donor type. Increased number of expanded clones compared to donor T-cell clones at Day +30 was associated with the incidence of acute GVHD (HR=1.11, p=5x10−5). Even after exclusion of the twelve patients who developed acute GVHD before Day +30, the association between acute GVHD and an increased clonal expansion at Day +30 remained (HR=1.098, p=0.041), indicating that increased clonal T-cell expansion preceded the development of acute GVHD. Our results highlight T-cell clonal expansion as a potential novel biomarker for acute GVHD that warrants further study.
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