Abstract
Type 1 diabetes is a common autoimmune disease due to destruction of pancreatic β cells, resulting in lifelong need for insulin. Evidence suggest that maintaining residual β-cell function can improve glucose control and reduce risk of hypoglycaemia and vascular complications. Non-clinical, preclinical and some preliminary clinical data suggest that low-dose interleukin-2 (IL-2) therapy could block pancreatic β cells destruction by increasing the number of functional regulatory T cells (Tregs) that inhibit islet-specific autoreactive effector T cells (Teffs). However, there is lack of data on the effect of low-dose IL-2 in newly diagnosed children and adolescents with T1D as well as lack of specific data on its potential effect on β-cell function. The ' Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD)' is a phase 2, multicentre, double-blind, randomised, placebo-controlled trial in children and adolescents (6-18 years; having detectable C-peptide) initiated within 6 weeks of T1D diagnosis. A total of 45 participants will be randomised in a 2:1 ratio to receive either ultra-low dose IL-2 (aldesleukin), at a dose of 0.2 x 10 6 IU/m 2 twice-weekly, given subcutaneously, or placebo, for 6 months. The primary objective is to assess the effects of ultra-low dose aldesleukin administration on endogenous β-cell function as measured by frequent home dried blood spot (DBS) fasting and post-prandial C-peptide in children and adolescents with newly diagnosed T1D. The secondary objectives are: 1) to assess the efficacy of regular dosing of aldesleukin in increasing Treg levels; 2) to confirm the clinical safety and tolerability of ultra-low dose aldesleukin; 3) to assess changes in the immune system indicating benefit or potential risk for future gains/loss in β-cell function and immune function; 4) to assess treatment effect on glycaemic control. Trial registration: EudraCT 2017-002126-20 (06/02/2019).
Highlights
Rationale for IL-2 treatment in type 1 diabetes Type 1 diabetes (T1D) is a common autoimmune disease primarily mediated by T cells responses against pancreatic islet β-cell autoantigens, leading to the destruction of β cells and lack of insulin secretion[1,2]
IL-2 therapy is currently being investigated in many diseases, including T1D13–30 and our own investigations have established the doses of IL-2 in T1D patients that stimulate T regulatory cells (Tregs) but not T effector cells (Teff)[23,24]
Achieving a good glycaemic control represents a main goal in the management of T1D, and insulin therapy remains the cornerstone of treatment[39]
Summary
Rationale for IL-2 treatment in type 1 diabetes Type 1 diabetes (T1D) is a common autoimmune disease primarily mediated by T cells responses against pancreatic islet β-cell autoantigens, leading to the destruction of β cells and lack of insulin secretion[1,2]. Most newly diagnosed patients still have sufficient insulin production to reduce risk of acute complications of T1D, such as hypoglycaemia, and long-term vascular complications[3,4] If this residual endogenous insulin secretion could be preserved, by inhibiting the autoimmune attack and improving β-cell fragility to a hostile immune and hyperglycaemic environment, many of these life-threatening complications could be potentially avoided and exogenous insulin requirements reduced[4]. The ability to respond to IL-2 differs between Treg and Teff cells, due to different expression levels of CD25 and the balance of their intracellular signalling molecules: Tregs have a ten-fold greater sensitivity to IL-2 compared to Teff cells, due to higher expression of the IL-2 receptor[6] This opens a therapeutic window for the use of ultra-low doses of IL-2 to enhance selectively the Treg response in patients with T1D or other autoimmune and inflammatory diseases[12]. IL-2 therapy is currently being investigated in many diseases, including T1D13–30 and our own investigations have established the doses of IL-2 in T1D patients that stimulate Tregs but not Teffs[23,24]
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