A tissue-engineered model of T-cell–mediated oral mucosal inflammatory disease

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, KCa3.1 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.