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

Asma El-Howati, Jake G Edmans, Martin E Santocildes-Romero, Lars Siim Madsen, Craig Murdoch, Helen E Colley
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Abstract

T-cell-mediated oral mucocutaneous inflammatory conditions including oral lichen planus (OLP) are common but development of new treatments aimed at relieving symptoms and controlling OLP progression are hampered by the lack of experimental models. Here, we developed a tissue-engineered oral mucosal equivalent (OME) containing polarised T-cells to replicate OLP pathogenesis. Peripheral blood CD4+ and CD8+ T-cells were isolated, activated and polarised into Th1 and cytotoxic T-cells (Tc). OME were constructed by culturing oral keratinocytes on an oral fibroblast-populated hydrogel to produce a stratified squamous epithelium. OME stimulated with IFN-γ and TNF-α or medium from Th1 cells caused increased secretion of inflammatory cytokines/chemokines. A model of T-cell-mediated inflammatory disease was developed by combining OME on top of a Th1/Tc-containing hydrogel, followed by epithelial stimulation with IFN-γ/TNF-α. T-cell recruitment towards 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/or via a mucoadhesive patch prevented cytokine/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.

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T细胞介导的口腔黏膜炎症的组织工程模型。
T细胞介导的口腔黏膜炎症(包括口腔扁平苔藓)很常见,但由于缺乏实验模型,旨在缓解症状和控制口腔扁平苔藓进展的新疗法的开发受到阻碍。在这里,我们开发了一种含有极化 T 细胞的组织工程口腔黏膜等效物(OME)来复制 OLP 的发病机制。我们分离、激活了外周血CD4+和CD8+T细胞,并将其极化为Th1和细胞毒性T细胞(Tc)。通过在口腔成纤维细胞填充的水凝胶上培养口腔角质细胞来构建 OME,以产生分层鳞状上皮。OME 在 IFN-γ 和 TNF-α 或 Th1 细胞培养基的刺激下会增加炎性细胞因子/趋化因子的分泌。通过在含 Th1/Tc 水凝胶上结合 OME,然后用 IFN-γ/TNF-α 刺激上皮,建立了 T 细胞介导的炎症模型。T细胞向上皮细胞招募与T细胞趋化吸引剂CCL5、CXCL9和CXCL10的分泌增加有关。组织学评估显示,组织损伤与裂解的天冬酶-3 和层粘连蛋白-5 表达的改变有关。用针对 JAK、KCa3.1 通道或溶液中的氯倍他索的抑制剂和/或通过粘液贴片进行治疗,可防止细胞因子/趋化因子的释放和组织损伤。这种疾病模型具有探究发病机制或作为新型疗法或治疗模式测试平台的潜力。
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