title: Type 1 diabetes immunotherapy using polyclonal regulatory T cells.
abstract: 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(+)CD127(lo/-)CD25(+) polyclonal Tregs (0.05 × 10(8) to 26 × 10(8) 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(+)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 Treg therapy.
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. jeff.bluestone@ucsf.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Fitch
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Shipra
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
authors.affiliation: Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Lares
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: KineMed Inc., Emeryville, CA 94608, USA.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Li
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: S Alice
authors.initials: SA
authors.lastname: Long
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Masiello
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Vinh
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Putnam
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Rieck
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sayre
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Tang
mesh_terms: D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult