T cell repertoire following autologous stem cell transplantation for multiple sclerosis
T cell repertoire following autologous stem cell transplantation for multiple sclerosis
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DOI：
10.1172/jci71691
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发表时间：
2014-03-01
影响因子：
15.9
通讯作者：
Turka, Laurence A.
中科院分区：
文献类型：
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作者：
Muraro, Paolo A.;Robins, Harlan;Turka, Laurence A.
自体造血干细胞移植(HSCT)常用于治疗血液系统和非血液系统的恶性肿瘤。在临床试验中，HSCT已被评估为严重的自身免疫，作为一种“重置”免疫系统的方法，并产生了一种新的非自身免疫谱系。虽然消除绝大多数成熟T细胞的可行性已经确立，但准确和定量地确定再生T细胞与基线谱系的关系一直很难评估。这里，在HSCT治疗预后不良的多发性硬化症的II期研究中，我们使用高通量深层TCRβ链测序来评估每个患者样本中数百万个单独的TCR。我们发现HSCT对CD4(+)和CD8(+)T细胞有明显的影响。在CD4(+)T细胞中，治疗前存在的主要TCR克隆在重建后无法检测到，患者在很大程度上发展了新的谱系。相反，优势的CD8(+)克隆没有被有效去除，重组的CD8(+)T细胞库是通过对治疗前存在的细胞进行克隆性扩增而产生的。重要的是，在重建过程的早期，对治疗无效的患者的T细胞谱系的多样性较小。这些结果表明，免疫调节治疗期间的TCR特征是可行的，也是信息丰富的，并且可以监测HSCT和细胞治疗后的致病或保护性T细胞克隆。
Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCR beta chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4(+) and CD8(+) T cell repertoires. In CD4(+) T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8(+) clones were not effectively removed, and the reconstituted CD8(+) T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies.