Decernotinib

T-cell-mediated oral mucocutaneous inflammatory conditions, including oral lichen planus, are common, but development of new treatments aimed at relieving symptoms and controlling oral lichen planus progression is hampered by the lack of experimental models. In this study, we developed a tissue-engineered oral mucosal equivalent containing polarized T-cells to replicate oral lichen planus pathogenesis. Peripheral blood CD4+ and CD8+ T-cells were isolated, activated, and polarized into T helper 1 and cytotoxic T cells. Oral mucosal equivalents were constructed by culturing oral keratinocytes on an oral fibroblast-populated hydrogel to produce a stratified squamous epithelium. Oral mucosal equivalent stimulated with IFN-γ and TNF-α or medium from T helper 1 cells caused increased secretion of inflammatory cytokines and chemokines. A model of T-cell-mediated inflammatory disease was developed by combining oral mucosal equivalent on top of a T helper 1 and cytotoxic T-cell-containing hydrogel, followed by epithelial stimulation with IFN-γ and TNF-α. T-cell recruitment toward the epithelium was associated with increased secretion of T-cell chemoattractants CCL5, CXCL9, and CXCL10. Histological assessment showed tissue damage associated with cleaved caspase-3 and altered laminin-5 expression. Treatment with inhibitors directed against Jak, K_Ca3.1 channels, or clobetasol in solution and through a mucoadhesive patch prevented cytokine and chemokine release and tissue damage. This disease model has potential to probe for mechanisms of pathogenesis or as a test platform for novel therapeutics or treatment modalities.

Guillain-Barré syndrome (GBS) is an auto-inflammatory peripheral nerve disease. Dendritic cell-mediated T cell polarization is of pivotal importance in demyelinating lesions of peripheral nerves and nerve roots. However, the regulatory function of VX-509 (Decernotinib)-modified tolerogenic dendritic cells (VX-509-tolDCs) during immune remodeling following GBS remains unclear. Here, we used experimental autoimmune neuritis (EAN) as a model to investigate these aspects of GBS.

DCs were treated with varying concentrations of VX-509 (0.25, 1, and 4 μM) or served as a control using 10^-8 M 1,25-(OH)₂D₃. Flow cytometry was employed to assess the apoptosis, phenotype, and capacity to induce T cell responses of the treated DCs. In the in vivo experiments, EAN mice received administration of VX-509-tolDCs or 1,25-(OH)₂D₃-tolDCs via the tail vein at a dose of 1x10⁶ cells/mouse on days 5, 9, 13, and 17.

VX-509 inhibited the maturation of DCs and promoted the development of tolDCs. The function of antigen-specific CD4 + T cells ex vivo was influenced by VX-509-tolDCs. Furthermore, the adoptive transfer of VX-509-tolDCs effectively alleviated inflammatory demyelinating lesions in EAN by promoting Th17/Treg (T helper 17 and regulatory T cells) rebalance.

The adoptive transfer of VX-509-tolDCs alleviated inflammatory demyelinating lesions in a mouse model of GBS, known as the EAN mouse, by partially restoring the balance between Treg and Th17 cells.