Sean N. Parker Autoimmune Research Laboratory and.
Diabetes Center, UCSF, San Francisco, California, USA.
JCI Insight. 2021 Sep 22;6(18):e147474. doi: 10.1172/jci.insight.147474.
BACKGROUNDA previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells.METHODSPatients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations' phenotypes over time.RESULTSMultiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations.CONCLUSIONThese data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity.TRIAL REGISTRATIONClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial).FUNDINGSean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.
一项前期 I 期研究表明，输注自体 Tregs 进行体外扩增后用于近期发病的 1 型糖尿病（T1D）患者，具有极佳的安全性。然而，在输注后 3 个月（Treg-T1D 试验），大多数输注的 Tregs 在外周血中无法检测到。因此，我们进行了一项 I 期研究（TILT 试验），联合使用多克隆 Tregs 和低剂量 IL-2，这被证明可以增强 Treg 的存活和扩增，并评估其对 Treg 群体和其他免疫细胞的影响随时间的变化。
T1D 患者接受单次输注自体多克隆 Tregs，随后接受一次或两次为期 5 天的重组人低剂量 IL-2（ld-IL-2）治疗。流式细胞术、飞行时间细胞术和 10x Genomics 单细胞 RNA-Seq 用于随时间追踪不同免疫细胞群体的表型。
多参数分析显示，联合治疗导致输注和内源性 Treg 数量增加，但也导致从基线开始，激活 NK、黏膜相关不变 T 和克隆性 CD8+T 细胞亚群显著增加。
这些数据支持以下假设，即 ld-IL-2 不仅可以扩增外源性给予的 Tregs，还可以扩增细胞毒性细胞。这些结果对使用 ld-IL-2 和 Tregs 联合治疗存在固有活性免疫的自身免疫性疾病具有重要意义。
ClinicalTrials.gov NCT01210664（Treg-T1D 试验），NCT02772679（TILT 试验）。
Sean N. Parker 自身免疫研究实验室基金，国家研究资源中心。
