BES2022 BES 2022 Abstracts (23 abstracts)
A plasma miR-193b-365 signature predicts non-responsiveness to Lactococcus lactis-based antigen- specific immunotherapy in new-onset type 1 diabetes
Sassi Gabriele 1,* , Licata Giada 2,* , Ventriglia Giuliana 2 , Ellis Darcy 1 , Van Damme Niels 3 , Saeys Yvan 3 , Caluwaerts Silvia 4 , Mori Alessia 2,3 , Rottiers Pieter 5 , Mathieu Chantal 1 , Dotta Francesco 2,3 , Gysemans Conny 1,** & Sebastiani Guido 2,**
1Clinical and Experimental Endocrinology, CHROMETA, KU Leuven, Leuven, Belgium; 2Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena; Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy; 3Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy; 4Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium; 5Precigen Actobio, Zwijnaarde (Ghent), Belgium; *shared first authorship; **shared senior authorship
Background and aims: Combining systemic immunomodulation with disease-relevant antigens could provide longer-term solutions for preventing and even reversing autoimmune type 1 diabetes (T1D). Our team established that a combination therapy (CT), composed of a short-course low-dose anti-CD3 treatment with oral delivery of genetically-modified Lactococcus lactis (L. lactis) bacteria secreting full proinsulin plus the anti- inflammatory cytokine IL-10 (LL-PINS+IL-10), was effective in reversing T1D in the non-obese diabetic (NOD) mouse model. Here, we aimed to identify robust peripheral biomarkers for prediction of CT response using circulating cell-free microRNAs (miRNAs). Furthermore, we exploited CITE-sequencing (CITE-seq), a multimodal phenotyping method that simultaneously measures RNA and cell surface proteins at single cell level to investigate the immune cell types as a possible source of the identified miRNA signature.
Materials and methods: New-onset diabetic NOD mice were injected intravenously with anti-CD3 (d0-5) and inoculated with LL-PINS+IL-10 for 6 weeks. TaqMan™ miRNA array followed by single-assay Q-PCR was performed on plasma samples taken from responder (R) and non-responder (NR) mice before CT initiation. CITE-seq was used to profile FACS-sorted circulating and pancreas-infiltrated CD45+ immune cells of new- onset diabetic NOD mice.
Results: Overall disease remission was 45% by the CT (n=110) compared to 0% in untreated controls (n=13; P<0.01) that remained hyperglycaemic. Using miRNA profiling, six miRNAs (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 R and NR mice at therapy initiation. Of those, miR-193b-3p and miR-365-3p were selected to compose, together with age and glycaemia status at disease onset, a signature able to predict therapy non-responsiveness with 83% specificity and 89% sensitivity. Both miRNAs were highly abundant at disease onset in pancreas- infiltrating neutrophils and basophils. CITE-seq analysis revealed a pro-inflammatory and activated phenotype in pancreas-infiltrated neutrophils and basophils compared to those in the bloodstream.
Conclusion: The miR-193b-365 signature could serve as a novel circulating prognostic biomarker for prospective personalised L. lactis-based immunotherapy in human new-onset T1D.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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