017 A novel therapeutic strategy using stabilized antigen-specific iTreg for pemphigus

Inducible regulatory T cell (iTreg) is highly expected to exert antigen-specific immunosuppression in autoimmune diseases. A major obstacle clinical application the functional instability of iTreg vivo that associated with gene methylation immunoregulatory molecules. To overcome this problem, here we generated stabilized (siTreg) by optimizing culture conditions CDK8/19 inhibitor and retinoid absence CD28 signaling. We applied novel method for pemphigus vulgaris, an disease caused anti-Dsg3 IgG, prepared siTreg Dsg3-specific receptor transgenic (H1) CD4 cells. RNA-seq analysis showed transcriptome much closer nTreg than conventional iTreg. In co-culture experiments, inhibited proliferation a dose-dependent manner, but hardly irrelevant Ova-specific proliferation. interface dermatitis model directly induced H1 effector cells, significantly reduced skin severity inhibiting IFN-γ production from Notably Foxp3 expression was maintained siTreg, not WT 2 weeks after transfusion. model, decreased scores circulating IgG titers. Moreover, ELISpot assay, B number lowered without influencing disease-unrelated humans, highly-demethylated patients’ PBMC, which response detected Dsg3 peptides. The human demonstrated inhibit autologous vitro. These studies mice humans epigenetically modified can maintain suppress both humoral cellular immunity manner. Thus, holds great potency development immunotherapy pemphigus.