Children's Cancer Research Institute, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.
Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria.
Front Immunol. 2019 Aug 27;10:1879. doi: 10.3389/fimmu.2019.01879. eCollection 2019.
Recent data revealed the importance of immune reconstitution (IR) for the evaluation of possible biomarkers in National Institutes of Health (NIH)-defined chronic graft-vs.-host disease (cGVHD) and its clinical aspects. In this large pediatric study ( = 146), we have analyzed whether cellular and humoral parameters of IR in the long-term follow-up (FU) with a special emphasis on B-cell reconstitution correlate with NIH-defined cGVHD criteria. HYPOTHESIS: we were especially interested in whether meaningful cGVHD biomarkers could be defined in a large pediatric cohort. We here demonstrate for the first time in a highly homogenous pediatric patient cohort that both cGVHD ( = 38) and its activity were associated with the perturbation of the B-cell compartment, including low frequencies of CD19CD27 memory B-cells and increased frequencies of circulating CD19CD21 B-cells, a well-known hyperactivated B-cell subset frequently found elevated in chronic infection and autoimmunity. Notably, resolution of cGVHD correlated with expansion of CD19CD27 memory B-cells and normalization of CD19CD21 B-cell frequencies. Moreover, we found that the severity of cGVHD had an impact on parameters of IR and that severe cGVHD was associated with increased CD19CD21 B-cell frequencies. When comparing the clinical characteristics of the active and non-active cGVHD patients (in detail at time of analyses), we found a correlation between activity and a higher overall severity of cGVHD, which means that in the active cGVHD patient group were more patients with a higher disease burden of cGVHD-despite similar risk profiles for cGVHD. Our data also provide solid evidence that the time point of analysis regarding both hematopoietic stem cell transplantation (HSCT) FU and cGVHD disease activity may be of critical importance for the detailed investigation of pediatric cohorts. Finally, we have proven that the differences in risk factors and patterns of IR, with cGVHD as its main confounding factor, between malignant and non-malignant diseases, are important to be considered in future studies aiming at identification of novel biomarkers for cGVHD.
最近的数据显示，免疫重建（IR）对于评估美国国立卫生研究院（NIH）定义的慢性移植物抗宿主病（cGVHD）及其临床方面的潜在生物标志物非常重要。在这项大型儿科研究（=146）中，我们分析了长期随访（FU）中 IR 的细胞和体液参数，特别强调 B 细胞重建，这些参数是否与 NIH 定义的 cGVHD 标准相关。假设：我们特别感兴趣的是，在大型儿科队列中是否可以定义有意义的 cGVHD 生物标志物。我们在这里首次在高度同质的儿科患者队列中证明，cGVHD（=38）及其活性与 B 细胞群的紊乱相关，包括 CD19CD27 记忆 B 细胞的频率降低和循环 CD19CD21 B 细胞的频率增加，这是一种众所周知的活化 B 细胞亚群，经常在慢性感染和自身免疫中升高。值得注意的是，cGVHD 的缓解与 CD19CD27 记忆 B 细胞的扩增和 CD19CD21 B 细胞频率的正常化相关。此外，我们发现 cGVHD 的严重程度对 IR 参数有影响，严重的 cGVHD 与 CD19CD21 B 细胞频率的增加有关。当比较活动期和非活动期 cGVHD 患者的临床特征（在分析时详细比较）时，我们发现活动期与 cGVHD 的总体严重程度较高相关，这意味着在活动期 cGVHD 患者组中，尽管 cGVHD 的风险状况相似，但患有更高 cGVHD 疾病负担的患者更多。我们的数据还提供了确凿的证据，表明造血干细胞移植（HSCT）FU 和 cGVHD 疾病活动的分析时间点对于儿科队列的详细研究可能至关重要。最后，我们已经证明，恶性和非恶性疾病之间，IR 的危险因素和模式的差异，cGVHD 是其主要混杂因素，在未来旨在确定 cGVHD 新生物标志物的研究中，这是需要考虑的重要因素。
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