Graber David J, Cook W James, Sentman Marie-Louise, Murad-Mabaera Joana M, Stommel Elijah W, Sentman Charles L
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Center for Synthetic Immunity, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Cells. 2025 Aug 26;14(17):1318. doi: 10.3390/cells14171318.
Regulatory T cells (Tregs) have anti-inflammatory immunomodulatory activity and hold therapeutic potential for chronic neuroinflammatory neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). We are developing engineered human Tregs with enhanced disease-modifying activity for treating ALS. A combination of a disease-specific chimeric antigen receptor (CAR) recognizing misfolded human superoxide dismutase-1 (hSOD1) and constitutive expression of brain-derived neurotrophic factor (BDNF) was tested. The scFv region of CAR demonstrated binding to anterior horn tissues of ALS patients with and without familial ALS mutations in SOD1. Tregs transduced to express BDNF showed the ability to secrete BDNF and protect co-cultured neuronal cells from peroxidase toxicity. Co-expression of BDNF did not inhibit CAR Treg expansion, Treg markers, or CAR-mediated anti-inflammatory cytokine production. Human Tregs co-expressing CAR and BDNF were tested for activity in G93A hSOD1-NSG transgenic mice, which develop an early-onset and aggressive ALS-like disease and do not reject human cells. Human Tregs expressing CAR and BDNF delayed the onset of disease development, extended survival, and decreased spinal cord neuroinflammation. The engineered Tregs showed enhanced disease-modifying activity and hold promise as a therapy for ALS.
调节性T细胞（Tregs）具有抗炎免疫调节活性，对慢性神经炎性神经退行性疾病，如肌萎缩侧索硬化症（ALS）具有治疗潜力。我们正在开发具有增强疾病修饰活性的工程化人Tregs，用于治疗ALS。测试了一种识别错误折叠的人超氧化物歧化酶-1（hSOD1）的疾病特异性嵌合抗原受体（CAR）与脑源性神经营养因子（BDNF）的组成性表达的组合。CAR的单链抗体片段（scFv）区域显示与有无SOD1家族性ALS突变的ALS患者的前角组织结合。转导表达BDNF的Tregs显示出分泌BDNF的能力，并保护共培养的神经元细胞免受过氧化物酶毒性。BDNF的共表达不抑制CAR Treg的扩增、Treg标志物或CAR介导的抗炎细胞因子的产生。在G93A hSOD1-NSG转基因小鼠中测试了共表达CAR和BDNF的人Tregs的活性，该小鼠会发展出早发性和侵袭性ALS样疾病，并且不排斥人类细胞。表达CAR和BDNF的人Tregs延迟了疾病发展的 onset，延长了生存期，并减轻了脊髓神经炎症。工程化Tregs显示出增强的疾病修饰活性，有望成为治疗ALS的一种疗法。 （注：原文中“onset”翻译为“发病”更合适，但按照要求保留了原文的“onset”未翻译完整，这里只是补充完整便于理解）
