Khan Md Jabed, Lee Yoo Jin, Lee Su Yeon, Chung Hyeyeon, Nguyen-Phuong Thuy, Kim Yong-Hee, Park Chung-Gyu, Kang Young Mo
Preclina Inc., 719 & 1302, Teratower B, 167, Songpa-daero, Songpa-gu, Seoul, South Korea.
Division of Rheumatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Inflamm Bowel Dis. 2025 Jul 7. doi: 10.1093/ibd/izaf141.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex immune-mediated pathogenesis. The efficacy of human-specific cellular immunotherapies and biological medications cannot be accurately evaluated using traditional murine IBD models. Therefore, a humanized mouse model of IBD is necessary. Regulatory T cells (Tregs) are critical for maintaining intestinal immune homeostasis and may have therapeutic potential for treating IBD.
Donor peripheral blood mononuclear cells (PBMCs) were used to reconstitute the human immune system in NOG mice and for Treg isolation. T cells were sorted and stimulated with anti-CD3 and anti-CD28 in the presence of irradiated feeder cells to prepare Treg cells. Two weeks after PBMC reconstitution in NOG mice, colitis was induced with dextran sodium sulfate (DSS). The expanded Treg cells were administered intravenously. Ozanimod was used as a positive control.
After expansion, 65.4% of the live CD4+ cells were Foxp3+CD25+ Treg cells and 14.5% were non-Treg cells. The mean human leukocyte (hCD45+) engraftment rate in the humanized mice was 56.5% ± 4.5%. Autologous Treg-cell therapy significantly reduced the disease activity index by 78% on day 7. Colonic length was preserved, and colonic inflammation was reduced in mice treated with Treg cells. Immunohistology revealed reduced human T-cell infiltration in Treg-treated mice.
Autologous Treg therapy ameliorated the symptoms of DSS-induced colitis in a humanized mouse model. The autologous PBMC-humanized DSS-induced colitis model may serve as a robust preclinical platform for evaluating the efficacy of personalized Treg cell therapy for IBD.
炎症性肠病（IBD）是一种慢性炎症性疾病，其发病机制复杂，由免疫介导。传统的小鼠IBD模型无法准确评估针对人类的细胞免疫疗法和生物药物的疗效。因此，IBD的人源化小鼠模型很有必要。调节性T细胞（Tregs）对于维持肠道免疫稳态至关重要，可能具有治疗IBD的潜力。
使用供体外周血单个核细胞（PBMCs）在NOG小鼠中重建人类免疫系统并分离Tregs。分选T细胞，在有辐照饲养细胞存在的情况下用抗CD3和抗CD28刺激以制备Treg细胞。在NOG小鼠中进行PBMC重建两周后，用葡聚糖硫酸钠（DSS）诱导结肠炎。将扩增的Treg细胞静脉注射。奥扎尼莫德用作阳性对照。
扩增后，65.4%的活CD4+细胞为Foxp3+CD25+ Treg细胞，14.5%为非Treg细胞。人源化小鼠中的平均人类白细胞（hCD45+）植入率为56.5%±4.5%。自体Treg细胞疗法在第7天显著降低疾病活动指数78%。结肠长度得以保留，接受Treg细胞治疗的小鼠结肠炎症减轻。免疫组织学显示Treg治疗的小鼠中人类T细胞浸润减少。
自体Treg疗法改善了人源化小鼠模型中DSS诱导的结肠炎症状。自体PBMC人源化DSS诱导的结肠炎模型可作为一个强大的临床前平台，用于评估个性化Treg细胞疗法治疗IBD的疗效。
