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A plasma miR-193b-365 signature combined with age and glycemic status predicts response to Lactococcus lactis-based antigen-specific immunotherapy in new-onset type 1 diabetes

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posted on 2023-07-26, 20:16 authored by Gabriele Sassi, Giada Licata, Giuliana Ventriglia, Amber Wouters, Pierre Lemaitre, Ruth Seurinck, Alessia Mori, Giuseppina Emanuela Grieco, Samal Bissenova, Darcy Ellis, Silvia Caluwaerts, Pieter Rottiers, Niels Vandamme, Chantal Mathieu, Francesco Dotta, Conny Gysemans, Guido Sebastiani

Immunomodulation combined with antigen therapy holds great promise to arrest autoimmune type 1 diabetes, but clinical translation is hampered by a lack of prognostic biomarkers. Low-dose anti-CD3 plus Lactococcus lactis (L. lactis) bacteria secreting proinsulin and IL-10 reversed new-onset disease in non-obese diabetic (NOD) mice, yet some mice were resistant to the therapy. Using microRNA (miRNA) profiling, six miRNAs (i.e., miR-34a-5p, miR-125a-3p, miR-193b-3p, miR-328, miR-365-3p, and miR-671-3p) were identified as differentially expressed in plasma of responder versus non-responder mice before study entry. After validation and stratification in an independent cohort, plasma miR-193b-3p and miR-365-3p combined with age and glycemic status at study entry had the best power to predict with high sensitivity and specificity poor response to the therapy. These miRNAs were highly abundant in pancreas infiltrating neutrophils and basophils with a pro-inflammatory and activated phenotype. Here, a set of miRNAs and disease-associated parameters are presented as predictive signature for the L. lactis-based immunotherapy outcome in new-onset type 1 diabetes, hence allowing targeted recruitment of future trial participants and accelerated trial execution. 

Funding

This work was supported by grants from the Research Foundation Flanders (FWO Vlaanderen, grant G.0C63.19N to Chantal Mathieu and Conny Gysemans, and FWO fellowship 1.1A02.20N for Samal Bissenova), the KU Leuven (C1/18/006), and by gifts for the Hippo & Friends type 1 diabetes and Carpe Diem funds for diabetes research.

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