Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Benaroya Research Institute, Seattle, Washington, USA.
J Clin Invest. 2024 Aug 13;134(18):e177492. doi: 10.1172/JCI177492.
BACKGROUNDTeplizumab, a non-FcR-binding anti-CD3 mAb, is approved to delay progression of type 1 diabetes (T1D) in at-risk patients. Previous investigations described the immediate effects of the 14-day treatment, but longer-term effects of the drug remain unknown.METHODSWith an extended analysis of study participants, we found that 36% were undiagnosed or remained free of clinical diabetes after 5 years, suggesting operational tolerance. Using single-cell RNA sequencing, we compared the phenotypes, transcriptome, and repertoire of peripheral blood CD8+ T cells including autoreactive T cells from study participants before and after teplizumab and features of responders and non-responders.RESULTSAt 3 months, there were transcriptional signatures of cell activation in CD4+ and CD8+ T cells including signaling that was reversed at 18 months. At that time, there was reduced expression of genes in T cell receptor and activation pathways in clinical responders. In CD8+ T cells, we found increased expression of genes associated with exhaustion and immune regulation with teplizumab treatment. These transcriptional features were further confirmed in an independent cohort. Pseudotime analysis showed differentiation of CD8+ exhausted and memory cells with teplizumab treatment. IL7R expression was reduced, and patients with lower expression of CD127 had longer diabetes-free intervals. In addition, the frequency of autoantigen-reactive CD8+ T cells, which expanded in the placebo group over 18 months, did not increase in the teplizumab group.CONCLUSIONThese findings indicate that teplizumab promotes operational tolerance in T1D, involving activation followed by exhaustion and regulation, and prevents expansion of autoreactive T cells.TRIAL REGISTRATIONClinicalTrials.gov NCT01030861.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases/NIH, Juvenile Diabetes Research Foundation.
Teplizumab 是一种非 FcR 结合的抗-CD3 mAb，被批准用于延缓高危患者的 1 型糖尿病 (T1D) 进展。先前的研究描述了 14 天治疗的即时效应，但药物的长期效应仍不清楚。
通过对研究参与者进行扩展分析，我们发现 36%的参与者在 5 年后仍未被诊断或未出现临床糖尿病，表明存在操作性耐受性。使用单细胞 RNA 测序，我们比较了 Teplizumab 治疗前后研究参与者外周血 CD8+T 细胞的表型、转录组和 repertoire，包括自身反应性 T 细胞，以及应答者和非应答者的特征。
在 3 个月时，CD4+和 CD8+T 细胞中存在细胞活化的转录特征，包括在 18 个月时逆转的信号。此时，临床应答者的 T 细胞受体和激活途径中的基因表达减少。在 CD8+T 细胞中，我们发现 Teplizumab 治疗后与衰竭和免疫调节相关的基因表达增加。这些转录特征在一个独立的队列中得到了进一步证实。拟时分析显示，Teplizumab 治疗后 CD8+衰竭和记忆细胞的分化。IL7R 表达减少，CD127 表达较低的患者无糖尿病间隔时间较长。此外，在安慰剂组中，18 个月内扩增的自身抗原反应性 CD8+T 细胞在 Teplizumab 组中没有增加。
这些发现表明，Teplizumab 在 T1D 中促进操作性耐受性，涉及激活后衰竭和调节，并防止自身反应性 T 细胞的扩增。
ClinicalTrials.gov NCT01030861。
美国国立卫生研究院国家糖尿病、消化和肾脏疾病研究所/美国国立卫生研究院、青少年糖尿病研究基金会。
