ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study used high-resolution single-cell multiomics and flow cytometry on blood samples from patients with type 1 diabetes (T1D) to examine the effects of low-dose recombinant IL-2 (iLD-IL-2). Administration of iLD-IL-2 expanded thymic-derived FOXP3⁺HELIOS⁺ Tregs and CD56^bright NK cells, reduced frequency of IL-21-producing CD4⁺T cells, and induced long-lived anti-inflammatory transcriptional changes in all T and NK cell subsets.

iLD-IL2 has been used in several inflammatory and autoimmune conditions based on the predominant stimulation of CD4⁺FOXP3⁺T regulatory cells (Tregs) that promote self-tolerance and prevent autoimmunity (1). Non-clinical, preclinical and clinical data suggest that iLD-IL2 therapy could prevent pancreatic β-cells destruction by increasing the number of functional Tregs (1). Small studies in adults with T1D have determined minimal effective doses and optimal frequency of iLD-IL2 administration [2,3].

This experimental study confirmed the safety of iLD-IL2, as indicated by a preferential expansion of HELIOS⁺Tregs and CD56^brNK cells and absence of cytotoxic gene expression signature in any T cell subset. Of particular interest was the effect of iLD-IL-2 in reducing IL-21-producing T cells. IL-21 has been implicated in the pathogenesis of several autoimmune diseases, such T1D, systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, and therefore the study findings further support the use of iLD-IL-2 use in these conditions. Furthermore, iLD-IL-2 induced prolonged transcriptional changes with anti-inflammatory properties in both T and NK cell subsets that were found one month after cessation of treatment. This suggests a longer treatment effect, which might be due to a binding of IL-2 to the extracellular matrix, leading to prolonged release even after the end of treatment.

Although the mechanisms underlining the long-lived gene expression signatures need to be clarified, this study provides further support for the safety and efficacy of iLD-IL-2. ILD-IL2 could be used as a combination strategy, along with other immunomodulatory/immunosuppressant agents, in early stages of clinical T1D or even to prevent diabetes in at risk individuals. Further support for the role of iLD-IL2 will hopefully come from the incoming results of a recently completed randomised controlled trial of iLD-IL2, administered every 3-4 days, to preserve β-cell function in children and adolescents with newly diagnosed T1D (4).

References: 1. Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol. 2015;15(5):283–294. 2. Seelig E, Howlett J, Porter L, et al. The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes. JCI Insight. 2018;3(19). 3. Todd JA, Evangelou M, Cutler AJ, et al. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. PLoS Med. 2016;13(10):e1002139. 4. Marcovecchio ML, Wicker LS, Dunger DB, et al. Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial. Wellcome Open Res. 2020;5:49. 10.12688/wellcomeopenres.15697.1.