Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial


An improper balance of regulatory/effector T (T reg /T eff ) cells is central to the development of autoimmune diseases, including type 1 diabetes. We previously showed that low-dose interleukin 2 (IL2) induced T reg 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 T reg 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 T eff cells by IL2 could exacerbate disease; and (3) the safety of low-dose IL2 is not known in type 1 diabetes.


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 T reg 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 .


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 T reg 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).


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 T reg cell increase would be desirable.


Assistance Publique-Hôpitaux de Paris, INSERM, and Pierre and Marie Curie Université.

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