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IMMUNOTHERAPY WITH LOW DOSE IL-2/CD25 PREVENTS BETA CELL DYSFUNCTION AND DYSGLYCEMIA IN PREDIABETIC NOD MICE

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posted on 2023-03-20, 15:13 authored by Farhan M. Qureshi, Julia K. Panzer, Janika Põder, Thomas R. Malek, Alejandro Caicedo

  

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.

Funding

This research was supported by NIH grants [F30DK126310 (F.M.Q.); R01AI148675 (T.R.M.); R01DK084321 (A.C.), R01DK111538 (A.C.), R01DK113093 (A.C.), U01DK120456 (A.C.), R33ES025673 (A.C.), and R01DK130328 (A.C.)] and the Leona M. and Harry B. Helmsley Charitable Trust grants G-2018PG-T1D034 (A.C.) and G-1912-03552 (A.C.).

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