供体来源的异体反应性T细胞在异基因造血干细胞移植（alloSCT）后的异体免疫反应中起着关键作用，包括预防复发的移植物抗白血病效应（GvL效应）和潜在致命的移植物抗宿主病（GvHD）并发症。通过去除T细胞来减少GvHD的风险，并通过引入额外的供体T细胞（供体淋巴细胞输注[DLI]）来增强GvL效应，可以改变GvL和GvHD之间的平衡。然而，T细胞动力学与异体免疫事件发生的关联尚未明确证明。因此，我们调查了166例接受基于alemtuzumab的T细胞耗竭（TCD）alloSCT的急性白血病患者队列中T细胞动力学和异体免疫反应之间的复杂关联。这些患者中，预计具有高复发风险的62例计划在移植后3个月接受预防性DLI。在这种情况下，我们应用联合建模方法，与传统统计方法相比，能更好地捕捉DLI、T细胞动力学、GvHD和复发之间的复杂相互作用。我们证明DLI可以引起可检测的T细胞扩增，从而导致自alloSCT后3个月开始的总T细胞、CD4+ T细胞和CD8+ T细胞计数的增加。CD4+ T细胞与异体免疫反应的发生呈最强的关联：CD4计数较高增加了GvHD的风险（风险比2.44，95%置信区间1.45-4.12），降低了复发的风险（风险比0.65，95%置信区间0.45-0.92）。类似的模型显示，自alloSCT后，自然杀伤细胞迅速恢复，并与复发的风险降低相关（风险比0.62，95%置信区间0.41-0.93）。本研究结果支持使用联合模型进一步研究不同环境中的免疫细胞动力学。版权所有© 2023 Koster, Bonneville, Borne, van Balen, Marijt, Tjon, Snijders, van Lammeren, Veelken, Putter, Falkenburg, Halkes和de Wreede。

Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings.Copyright © 2023 Koster, Bonneville, Borne, van Balen, Marijt, Tjon, Snijders, van Lammeren, Veelken, Putter, Falkenburg, Halkes and de Wreede.