Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Low-dose IL-2 for treatment and prevention of Type 1 Diabetes (#61)

David Klatzmann 1
  1. Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, INSERM and CNRS; Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy department (I2B), Hôpital Pitié-Salpêtrière, Paris, France

Most autoimmune diseases, including type 1 diabetes (T1D), are linked to an imbalance between auto-aggressive effector T cells (Teff) and regulatory T cells (Tregs) that normally control them. While blocking Teff with immunosuppressants has long been the only therapeutic option, activating/expanding Tregs may achieve the same purpose without the toxicity and side effects of immunosuppression.

We recently showed that low-dose interleukin-2 (LD IL-2) could safely expand/activate Tregs and likewise provide clinical improvement in patients with a vasculitis caused by chronic hepatitis C virus infection (Saadoun et al., NEJM 2011). We then aimed to determine which low-doses of IL-2 would be safe and produce desirable immunological changes in T1D patients. We thus performed a placebo-controlled dose-finding study of LD IL-2 in adult T1D patients.

We now report that IL-2 low doses of 0.33, 1 and 3 millions IU/day, given for 5 consecutive days, were very well tolerated and did not induce deleterious changes in glucose-metabolism parameters. They induced a dose-dependent increase in Treg numbers and proportions, with no significant increase or activation of Teff or NK cells. In treated patients, Tregs upregulated activation markers and basal pSTAT5 expression. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and TH17 inflammatory cells were mostly unchanged up to the dose of 1 million IU/day. Noteworthy, we observed blunting of the Teff responses against b-cell antigens in some treated patients. Thus, LD IL-2 is safe and fosters a dose-dependent Treg-oriented milieu in patients with type 1 diabetes (T1D). These results warrant further development of LD IL-2 for therapy and prevention of T1D.