التفاصيل البيبلوغرافية
| العنوان: |
A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes. |
| المؤلفون: |
Bender, Christine, Wiedeman, Alice E., Hu, Alex, Ylescupidez, Alyssa, Sietsema, William K., Herold, Kevan C., Griffin, Kurt J., Gitelman, Stephen E., Long, S. Alice |
| المصدر: |
Science Translational Medicine; 5/8/2024, Vol. 16 Issue 746, p1-15, 15p |
| مصطلحات موضوعية: |
REGULATORY T cells, TYPE 1 diabetes, AUTOIMMUNE diseases, INSULIN pumps, IMMUNOLOGICAL tolerance, CELL physiology, RNA sequencing |
| مستخلص: |
CD4+CD25hiCD127lo/−FOXP3+ regulatory T cells (Tregs) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal Tregs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded Tregs (expTregs) in a randomized phase 2 multi-center, double-blind, clinical trial (Sanford/Lisata Therapeutics T-Rex phase 2 trial, ClinicalTrials.gov NCT02691247). One hundred ten treated children and adolescents with new-onset T1D were randomized 1:1:1 to high-dose (20 × 106 cells/kilogram) or low-dose (1 × 106 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expTregs and peripheral blood samples from participants. The single doses of expTregs were safe but did not prevent decline in residual β cell function over 1 year compared to placebo (P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpTregs were highly activated and suppressive in vitro. A transient increase of activated memory Tregs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expTregs. However, the in vitro fold expansion of expTregs varied across participants, even when accounting for age, and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of Treg dose. These results suggest that a single dose of polyclonal expTregs does not alter progression in T1D; instead, Treg quality may be an important factor. Editor's summary: Regulatory T cells (Tregs) are important in immune tolerance. Infusion of autologous polyclonal Tregs, first expanded in vitro to increase their numbers, has been investigated for safety in small clinical studies, however usefulness of this therapy for type 1 diabetes (T1D) remains unclear. Bender et al. report that a phase 2 randomized trial of a single dose of expanded Tregs showed no efficacy in preserving C-peptide, an indicator of β cell function, in early-onset T1D. This negative in vivo result comes despite the suppressive capacity of the expanded Tregs in vitro, and will inform future studies of the role of polyclonal Tregs in T1D. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
