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Clinical MedicineIn-Press PreviewAutoimmunityEndocrinology Open Access | 10.1172/JCI177492
1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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1Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, United States of America
2Benaroya Research Institute, Seattle, United States of America
3Center for Systems and Engineering Immunology and Department of Immunobiolo, Yale University School of Medicine, New Haven, United States of America
4NIH Center for Human Immunology, NIH, Bethesda, United States of America
5Department of Biomedical Engineering, Yale University, New Haven, United States of America
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Published August 13, 2024 - More info
BACKGROUND. Teplizumab, a FcR non-binding anti-CD3 mAb, is approved to delay progression of type 1 diabetes (T1D) at-risk patients. Previous investigations described the immediate effects of the 14-day treatment, but longer-term effects of the drug remain unknown.
METHODS. With an extended analysis of study participants, we found that 36% were undiagnosed or remained clinical diabetes free after 5 years suggesting operational tolerance. Using single cell RNA-seq, 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.
RESULTS. At 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, that expanded in the placebo group over 18 months, did not increase in the teplizumab group.
CONCLUSION. These findings indicate that teplizumab promotes operational tolerance in T1D, involving activation followed by exhaustion and regulation and prevents expansion of autoreactive T cells.
TRIAL REGISTRATION. ClinicalTrials.gov: NCT01030861.
FUNDING. NIDDK/NIH, Juvenile Diabetes Research Foundation.