Abstract
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 beta cell function that has long-term implications for disease pathogenesis. Yet, to date, the effects of IL-2/CD25 on beta 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 beta 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 beta cells became more robust and synchronous, indicating that changing the local immune cell infiltrate with IL-2/CD25 preserved beta cell function even after treatment cessation. Our study thus provides mechanistic insight and serves as a stepping stone for future research using low-dose IL-2/CD25 immunotherapy in patients.
