Zucchi Elisabetta, Banchelli Federico, Simonini Cecilia, De Biasi Sara, Martinelli Ilaria, Gianferrari Giulia, Lo Tartaro Domenico, Cossarizza Andrea, D'Amico Roberto, Mandrioli Jessica
Neuroscience PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
Department of Neurosciences, Ospedale Civile di Baggiovara, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
Front Immunol. 2025 Jan 8;15:1508974. doi: 10.3389/fimmu.2024.1508974. eCollection 2024.
T regulatory cells (Tregs) inversely correlate with disease progression in Amyotrophic Lateral Sclerosis (ALS) and fast-progressing ALS patients have been reported to exhibit dysfunctional, as well as reduced, levels of Tregs. This study aimed to evaluate the longitudinal changes in Tregs among ALS patients, considering potential clinical and biological modifiers of their percentages and concentrations. Additionally, we explored whether measures of ALS progression, such as the decline over time in the revised ALS Functional Rating Scale (ALSFRS-r) or forced vital capacity (FVC) correlated Treg levels and whether Treg phenotype varied during the course of ALS.
Total Tregs (detected by CD3, CD4, FoxP3, CD25, and CD127) were quantified at five time points over 54 weeks in 21 patients in the placebo arm of the RAP-ALS trial; next they were characterized for the expression of surface markers including CD38, CD39, CXCR3, and PD1. Repeated measures mixed models were used to analyze the longitudinal course of Tregs, considering potential associations with other clinical and laboratory characteristics. Correlations between ALSFRS-r or FVC and Tregs over time were similarly investigated.
Our study showed that Treg levels did not change significantly on average during the observation period in our ALS cohort. However, PD1+Tregs decreased and CD39+Tregs increased over time. Male sex and cholesterol levels were associated with increasing Tregs (%) over time, while monocytes positively affected Treg concentrations. Treg concentrations showed a modesty association with FVC decline but were not associated with ALSFRS-r decline.
Treg levels remained stable during the ALS observation period and were not significantly associated with ALSFRS-r variations, suggesting that Treg numbers alone may have limited utility as a pharmaco-dynamic biomarker for ALS trials. However the observed changes in Treg phenotypes, such as the decrease in PD1+Tregs, indicate that phenotypic variations may warrant further investigation for their potential role in ALS progression and therapeutic targeting.
调节性T细胞（Tregs）与肌萎缩侧索硬化症（ALS）的疾病进展呈负相关，据报道，快速进展的ALS患者表现出功能失调以及Tregs水平降低。本研究旨在评估ALS患者中Tregs的纵向变化，同时考虑其百分比和浓度的潜在临床及生物学调节因素。此外，我们还探讨了ALS进展的指标，如修订的ALS功能评定量表（ALSFRS-r）随时间的下降或用力肺活量（FVC）与Treg水平是否相关，以及Treg表型在ALS病程中是否发生变化。
在RAP-ALS试验安慰剂组的21例患者中，于54周内的五个时间点对总Tregs（通过CD3、CD4、FoxP3、CD25和CD127检测）进行定量；接下来对其表面标志物包括CD38、CD39、CXCR3和PD1的表达进行表征。采用重复测量混合模型分析Tregs的纵向变化过程，同时考虑与其他临床和实验室特征的潜在关联。类似地，研究了随时间推移ALSFRS-r或FVC与Tregs之间的相关性。
我们的研究表明，在我们的ALS队列观察期内，Treg水平平均没有显著变化。然而，随着时间的推移，PD1+Tregs减少，CD39+Tregs增加。男性和胆固醇水平与Tregs（%）随时间增加相关，而单核细胞对Treg浓度有正向影响。Treg浓度与FVC下降呈适度相关，但与ALSFRS-r下降无关。
在ALS观察期内Treg水平保持稳定，且与ALSFRS-r变化无显著关联，这表明仅Treg数量作为ALS试验的药效学生物标志物可能效用有限。然而，观察到的Treg表型变化，如PD1+Tregs的减少，表明表型变异可能因其在ALS进展和治疗靶点中的潜在作用而值得进一步研究。
