Type 1 Diabetes (T1D) is hallmarked by beta-cells destruction. We aimed to identify specific pancreatic microRNAs (miRNA) as potential biomarkers for T1D prediction and diagnosis, and IgM treatment effectiveness.

Methods: The study included non-obese diabetic (NOD) mice (n=39) at different age and T1D stage. NOD mice were treated with IgM (n=15) or vehicle (saline; n=24) intraperitoneally and underwent pancreatectomy at 5-weeks (5wk, n=10), 14-weeks (14wk, n=15), and 21-weeks (21wk, n=14). T1D progression was categorized by serum glucose: normal (>120mg/dL), hyperglycemia (120-250mg/dL), and diabetes (>250mg/dL). Total RNA was isolated from pancreatic tissue, labeled, and used for GeneChip miRNA v3.0 array hybridization. Probeset summaries were obtained using RMA algorithm. Two-sample t-test was fit for pairwise comparisons. P≤0.01 was considered significant. IPA tool was used for biological analyses. Significant and biologically relevant miRNAs were validated by RT-PCR.

Results: For non-treated mice, there was a significant increase in glycaemia at 14wk (p=0.005) and 21wk (p>0.001). In contrast, glycaemia in IgM-treated mice remained similar at 5wk (135mg/dL) at 14wk (114mg/dL) and 21wk (113mg/dL). For non-treated mice, onset of diabetes occurred at 14wk. In total, 39 miRNAs were found to be differentially expressed when comparing 5wk vs. 21wk. Differentially expressed miRNA profiles were identified in non-treated (39 miRNAs) and IgM-treated (42 miRNAs) mice between 5wk and 21wk. A comparison between profiles identified mature miRNAs specific for T1D (17 miRNAs) and IgM-treated (30 miRNAs) mice. Downregulated T1D specific miRNAs (mir-17-5p, -31-5p, -103-3p, and -379-5p) were related to pancreatic disorders and hyperglycemia. Upregulated IgM-treatment specific miRNAs (mir-155-5p, -21-5p, 16-5p, and 10a-5p) were associated with induction of monocytic and polymorphonuclear myeloid derived suppression cells and immunomodulation. Four miRNAs (miR-1224, -130b, -150, and -29a) overlapped between groups. The differential expression of MiR-150 (which modulates B and T cells) was 7.6-fold higher in IgM-treated mice. Selected miRNAs (n=11) including miR-29a, -150, -31, and -103 were validated.

Conclusions: Intraperitoneal IgM inoculation promoted normal glycaemia and upregulated immune-modulatory miRNAs in DT1 compromised mice. This findings may be the basis for new strategies for individuals at risk for DT1 and patients undergoing islet cells transplantation.

CITATION INFORMATION: Chhabra P, Gehrau R, Mas V, Bower D, Maluf D, Brayman K. IgM Treatment Successfully Prevents Type 1 Diabetes by Dysregulation of Pancreatic MicroRNAs with Immunomodulatory Roles. Am J Transplant. 2016;16 (suppl 3).

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