dose finding study of il-2 at ultra-low dose in children with recently diagnosed type 1 diabetes

Conditions: Type 1 Diabetes

Summary: 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

Keywords: recently diagnosed regulatory t cells tolerance induction paediatrics low dose il-2