Type 1 diabetes immunotherapy using polyclonal regulatory T cells

Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (T-regs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace T-regs in T1D may reverse autoimmunity and protect the remaining insulin-producing beta cells. On the basis of this premise, a robust technique has been developed to isolate and expand T-regs from patients with T1D. The expanded T-regs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of T-reg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo-expanded autologous CD4(+)CD127(lo/-)CD25(+) polyclonal T-regs (0.05 x 10(8) to 26 x 10(8) cells). A subset of the adoptively transferred T-regs 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 T-regs in recipients and retained a broad T-reg FOXP3(+)CD4(+)CD25(hi)CD127(lo) 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 T-reg therapy.