Oral vaccination with Fc-coupled preproinsulin prevents T1D

Background. Tolerogenic vaccinations using beta-cell antigens (Ags) targeted by autoimmune T-cells are attractive for T1D prevention due to their selectivity and safety, but have not hold their promise in clinical trials. This is probably due to the late time of intervention, once the autoimmune reaction is already on going. We therefore devised a strategy to introduce the triggering Ag preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy takes advantage of an Fc-fused PPI (PPI-Fc), which can be transported across the intestinal epithelium through the neonatal Fc receptor (FcRn), the pathway that physiologically delivers maternal antibodies to the offspring.

Methods. PPI-Fc was orally administered to 1-day-old G9C8 NOD mice, which are transgenic for a TCR recognizing the PPI-B15-23 epitope. PPI-Fc transfer through the gut epithelium was documented by in vivo imaging, confocal microscopy and ELISA. Its cellular uptake by lamina propria Ag-presenting cells and subsequent effects on pathogenic and regulatory T-cells were followed along with diabetes incidence at the adult age.

Results. One single PPI-Fc oral dose prevented diabetes in G9C8 NOD mice. PPI-Fc was efficiently transferred through the gut epithelium via the FcRn pathway. It was taken up by macrophages and migratory dendritic cells in the lamina propria and reached the thymus. This bio-distribution was associated with a decrease in PPI-reactive CD8+ T-cells and an increase in thymic-derived CD4+ Tregs 4 weeks after treatment. Oral PPI-Fc vaccination proved superior to Fc-devoid PPI at all these steps and may represent a novel strategy for T1D prevention in auto-antibody-positive and genetically at-risk relatives.