title: Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  An improper balance of regulatory/effector T (Treg/Teff) cells is central to the development of autoimmune diseases, including type 1 diabetes. We previously showed that low-dose interleukin 2 (IL2) induced Treg cell expansion and activation and clinical improvement in patients with hepatitis-C-virus-induced vasculitis. We aimed to establish which low doses of IL2 would be safe and induce Treg cells in patients with type 1 diabetes, considering that: (1) type 1 diabetes might be linked to alteration of the IL2/IL2R activation pathway; (2) activation of pathogenic Teff cells by IL2 could exacerbate disease; and (3) the safety of low-dose IL2 is not known in type 1 diabetes.
  
  
  METHODS
  This was a single-centre phase 1/2 study. 24 adult patients (18-55 years) with established insulin-dependent type 1 diabetes and at least one diabetes-related autoantibody were enrolled and randomly assigned (in a 1:1:1:1 ratio, by computer-generated randomisation list, with block size four) to placebo or IL2 at 0.33 MIU/day, 1 MIU/day, or 3 MIU/day for a 5-day course and were followed up for 60 days. All investigators and participants were masked to assignment. The primary outcome was change in Treg cells, measured by flow cytometry, and expressed as a percentage of CD4+ T cells, from day 1 to day 60. This trial is registered with ClinicalTrials.gov, number NCT01353833.
  
  
  RESULTS
  Six patients were assigned to each group between June 1, 2011, and Feb 3, 2012. IL2 was well tolerated at all doses, with no serious adverse events. However, there was a dose-response association for non-serious adverse events during the treatment phase (days 1-6); one patient in the placebo group, three patients in the 0.33 MIU group, five patients in the 1 MIU group, and six patients in the 3 MIU group had non-serious adverse events. The most common adverse events in the treatment phase were injection-site reaction (no patients with placebo vs three patients with 0.33 MIU and 1 MIU vs two patients with 3 MIU) and influenza-like syndrome (no patients with placebo vs one patient with 0.33 MIU and 1 MIU vs four patients with 3 MIU). After the treatment phase, adverse events did not differ between groups. IL2 did not induce deleterious changes in glucose-metabolism variables. IL2 induced a dose-dependent increase in the proportion of Treg cells, significant at all doses compared with placebo (placebo mean increase 0.5% [SD 0.4]; 0.33 MIU 2.8% [1.2], p=0.0039; 1 MIU 3.9% [1.8], p=0.0039; 3 MIU 4.8% [1.9] p=0.0039).
  
  
  CONCLUSIONS
  We have defined a well-tolerated and immunologically effective dose range of IL2 for application to type 1 diabetes therapy and prevention, which could be relevant to other disorders in which a Treg cell increase would be desirable.
authors.affiliation: Department of Diabetology, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Hartemann
authors.affiliation: Department of Clinical Pharmacology, Hôpital Pitié-Salpêtrière, Paris, France; Pharmacologie, Paris, France.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bensimon
authors.affiliation: Department of Clinical Pharmacology, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Payan
authors.affiliation: Department of Diabetology, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Jacqueminet
authors.affiliation: Department of Diabetology, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bourron
authors.affiliation: Clinical Investigation Center Paris-Est-CIC-9304, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nicolas
authors.affiliation: Department of Biochemistry, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Fonfrede
authors.affiliation: Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Immunology-Immunopathology-Immunotherapy UPMC Univ Paris 06, Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy, Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy, Paris, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
authors.affiliation: Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Immunology-Immunopathology-Immunotherapy UPMC Univ Paris 06, Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy, Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Bernard
authors.affiliation: Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Immunology-Immunopathology-Immunotherapy UPMC Univ Paris 06, Paris, France; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy, Paris, France; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy, Paris, France. Electronic address: david.klatzmann@upmc.fr.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
mesh_terms: D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D007376:Interleukin-2