Low-dose IL-2 is a promising immunotherapy in clinical trials for treating type 1 diabetes. A new IL-2 analog, IL-2/CD25 fusion protein, has been shown to more efficiently delay or prevent diabetes in NOD mice by expanding the population of activated regulatory T cells. This therapy is intended for use before clinical diagnosis, in the early stages of type 1 diabetes progression. During this prediabetic period, there is a chronic decline in β-cell function that has long-term implications for disease pathogenesis. Yet, to date, the effects of IL-2/CD25 on β-cell function have not been evaluated. In this study, we treated prediabetic NOD mice with low-dose mouse IL-2/CD25 over 5 weeks and determined its impact on β-cell function. This treatment limited the progressive impairment of glucose tolerance and insulin secretion typical of the later stages of prediabetes. Intracellular Ca2+ responses to glucose in β-cells became more robust and synchronous, indicating that changing the local immune cell infiltrate with IL-2/CD25 preserved β-cell function even after treatment cessation. Our study thus provides mechanistic insight and serves as a steppingstone for future research using low-dose IL-2/CD25 immunotherapy in patients.
Immunotherapies such as IL-2/CD25 are known to prevent or delay diabetes. However, their impact on individual β-cell function is not yet understood.
Female NOD mice progress from stage 1 to 2 pre–type 1 diabetes between 12 and 17 weeks. Treatment with mouse IL-2 (mIL-2)/CD25 prevents this progression even after treatment cessation.
Individual β-cell function (measured via intracellular Ca2+ responses to glucose) declines during the pathogenesis of type 1 diabetes. Treatment with mIL-2/CD25 therapy limits β-cell dysfunction, and function continues to improve after treatment cessation.
Insulin secretion is improved with mIL-2/CD25 therapy.
This article contains supplementary material online at https://doi.org/10.2337/figshare.22280644.