Reversal of Diabetes in NOD Mice by Clinical-Grade Proinsulin and IL-10–SecretingLactococcus lactisin Combination With Low-Dose Anti-CD3 Depends on the Induction of Foxp3-Positive T Cells

• DOI: 10.2337/db15-1625
• Publication Date: 2016-11-09T12:14:27Z
• Authors: Tatiana Takiishi; Dana Paulina Cook; Hannelie Korf; Guido Sebastiani; Francesca Mancarella; João Paulo Montei...; Clive Wasserfall; Noelia Casares; Juan José Lasarte; Lothar Steidler; Pieter Rottiers; Francesco Dotta; Conny Gysemans; Chantal Mathieu
• Keywords: Proinsulin; NOD mice

The introduction of β-cell autoantigens via the gut through Lactococcus lactis (L. lactis) has been demonstrated to be a promising approach for diabetes reversal in NOD mice. Here we show that combination therapy low-dose anti-CD3 with clinical-grade self-containing L. lactis, appropriate human application, secreting proinsulin and interleukin-10, cured 66% mice new-onset diabetes, which is comparable results plasmid-driven lactis. Initial blood glucose concentrations (<350 mg/dL) insulin autoantibody positivity were predictors stable hyperglycemia, decline was an immune biomarker therapeutic outcome. assessment changes induced by lactis–based revealed elevated frequencies CD4+Foxp3+ T cells pancreas-draining lymph nodes, pancreas, peripheral all treated mice, independent metabolic Neutralization cytotoxic T-lymphocyte antigen 4 transforming growth factor-β partially abrogated suppressive function therapy-induced regulatory (Tregs). Ablation or functional impairment Foxp3+ Tregs vivo at start stop impaired tolerance, highlighting dependence tolerance on presence functionality cells. Biomarkers identified this study can potentially used future tailor individual patients.