Dose Finding Study of Il-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes

Human recombinant interleukin-2 (rhIL-2) is a biological signalling protein playing a key role in the regulation of the immune system. At high doses, rhIL-2 activates the immune effectors T cells (TEFFS) while at low doses rhIL-2 induces and activates regulatory T cells (TREGS), a population of immune cells controlling the immune Teff response. In patients with Type 1 Diabetes (T1D), TREGS fail to control the autoimmune destruction by TEFFS of pancreatic beta-cells producing insulin. The investigator recently showed that rhIL-2 at low dose is well tolerated in patients with an autoimmune disease and in adults with established T1D, inducing TREGS without effects on TEFFS. The investigators aim to use rhIL-2 at low dose to induce/stimulate TREGS in young recently diagnosed T1D patients. This study will investigate the dose effect relationship of low dose rhIL-2 on TREG induction such as to optimize the risk benefit ratio of this treatment in T1D. Through Treg induction, the investigators aim to protect the remaining/regenerating pancreatic β-cells from autoimmune destruction, thus improving or even curing T1D.

Main objective:

Define the lowest dose of rhIL-2 inducing TREGS in children with recently diagnosed type 1 diabetes.

Conduct of the study:

Three doses will be studied versus placebo in parallel groups of six patients. Each dose or placebo will be studied according to three periods of treatment:

1. Induction of TREGS following a cure of 5 days repeated once daily administration \[day 1 - day 5\].
2. Maintenance of TREGS following repeated administration once every two weeks for one year \[day 15 - day 337\].

At each treatment period, Treg response and tolerance will be evaluated. In addition, overall response on T1D parameters will be assessed throughout the study.

Eligibility Criteria:
Inclusion criteria :

* Age \[7-13\] years for girls and \[7-14\] years for boys

  * With a T1D diagnosis (as ADA)
  * Treated with insulin for ≤ 3 months,
  * With at least one auto-antibody among: anti-insulin, anti-GAD, anti-IA2, anti-ZnT8 ;
* No clinically relevant abnormal findings for haematology, biochemistry, liver and kidney functions
* Informed consent signed by the patient, the parents, and the investigator before any intervention necessary for the trial.

Exclusion criteria :

* Contra-indications to IL-2 :

  * Hyper sensibility to IL-2 or its excipients,
  * Severe cardiopathy
  * Previous organ allograft
  * Ongoing infection requiring antibiotherapy,
  * O2 Saturation ≤ 90 %
  * Severe impairment of any vital organ
  * Documented history of other auto-immune diseases (except for auto-antibodies for, IAA, GADA, IA-2A, anti-ZnT8A, and stable thyroiditis with normal TSH (\<10 mUI/L), T3 and, T4 levels.
  * Diabetes onset characteristics including:

    * Continuous nocturnal polyuria ≥ 3 months ;
    * Inaugural acidosis (with venous Ph \< 7.25) ;
    * HbA1c at diagnostic ≥ 13%;
    * Weight loss ≥ 10 % at diagnosis ;
    * Positive autoantibodies to 21-hydroxylase
    * Stage 2 obesity
* Non authorized concomitant treatment : immuno-modulators, cytotoxic drugs, drug modifying plasma glycemia
* vaccination ≤ 4 weeks with life vaccin
* Positive serology (IgM) to the Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV), reflecting an acute infection.
* Participation to another clinical investigation in previous 3 months
* No affiliation to National Health Insurance