Type 1 diabetes immunotherapy using polyclonal regulatory T cells
By J. Bluestone, J. Buckner, M. Fitch, S. Gitelman, Shipra Gupta, M. Hellerstein, K. Herold, A. Lares, Michael R. Lee, Kelvin W. Li and 8 more. Science Translational Medicine, 2015
950 citations recorded by the source corpus.
Autologous regulatory T cells can be expanded and are well tolerated in patients with recent-onset type 1 diabetes. Regulating type 1 diabetes In patients with type 1 diabetes (T1D), immune cells attack the insulin-producing β cells of the pancreas. The resulting prolonged increase in blood sugar levels can lead to serious complications including heart disease and kidney failure. Regulatory T cells (Tregs) have been shown to be defective in autoimmune diseases. Now, Bluestone et al. report a phase 1 trial of adoptive Treg immunotherapy to repair or replace Tregs in type 1 diabetics. The ex vivo–expanded polyclonal Tregs were long-lived after transfer and retained a broad Treg phenotype long-term. Moreover, the therapy was safe, supporting efficacy testing in further trials. Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing β cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo–expanded autologous CD4+CD127lo/−CD25+ polyclonal Tregs (0.05 × 108 to 26 × 108 cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3+CD4+CD25hiCD127lo phenotype long-term. There were no infusion reactions or cell therapy–related high-grade adverse events. C-peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy.
Subfields: Genetics, Immunology, Surgery
View Paper: https://www.semanticscholar.org/paper/1ecfa9ce4e08156730177eee00656f699a8f1dc5
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Citations in the corpus
- HLA variation and disease (2018, background): “In the context of autoimmune disease and transplantation, pilot studies and early trials of the adoptive transfer of autologous, polyclonal T reg cells have provided support for the safety and possible capacity of these cells to induce tolerance in vivo 119,120 .”
- Regulatory T Cells and Human Disease. (2020, background): “Stimulation of TNFR2 by specific antibodies or agonists preferentially expanded natural Tregs in vivo and in vitro and has been shown to be effective in treating GVHD (161).”