Diabetes and other autoimmune endocrine diseases
Tolerogenic vaccinations with beta-cell antigens are attractive for type 1 diabetes (T1D) prevention, but have not hold their promise in clinical trials. This is probably because they have been implemented too late, i.e. in auto-antibody positive individuals with an autoimmune reaction already ongoing. We therefore devised a strategy to introduce the triggering antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy relies on an oral vaccine with Fc-fused PPI (PPI-Fc), which can cross the intestinal epithelium through the neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring.
One single oral PPI-Fc dose was administered to 1-day-old G9C8 NOD mice transgenic for a PPI-specific TCR, resulting in superior diabetes prevention compared to Fc-devoid PPI. In vivo imaging, confocal microscopy and flow cytometry documented that 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 gut lamina propria, but it was also measurable in the serum. PPI-Fc reached the thymus, where it colocalized with dendritic cells. This systemic bio-distribution was associated with a decrease in PPI-reactive effector CD8+ T-cells and with an increase in thymic-derived Foxp3+ regulatory T cells 4 weeks after treatment. Oral PPI-Fc proved superior to Fc-devoid PPI at all these steps. It may thus provide a novel strategy for T1D prevention in genetically at-risk individuals.