基于T细胞自噬调控的小分子环肽Roseotoxin B改善接触性皮炎的机制研究

发布时间：2018-04-28 00:41

本文选题：基于 + 细胞　；参考：《南京大学》2017年硕士论文

【摘要】：过敏性接触性皮炎(Allergic ContactDermatitis,ACD)是一种主要由T细胞介导的迟发型超敏反应。其临床症状主要表现为起疱、水肿和红斑等,目前通常采用环孢霉素A和糖皮质激素等进行治疗。尽管这些免疫抑制剂能够有效地调节机体免疫过程中的过度反应,缓解疾病症状,但是选择性较差,常出现不良反应。因此,寻找更高选择性地针对过度活化T细胞的候选药物显得尤为迫切。前期研究发现,粉红单端胞霉菌(Trichotheciumroseum fungus)发酵代谢产物中分离纯化得到的小分子环肽RoseotoxinB具有独特的免疫抑制功能。因此,我们尝试在小鼠接触性皮炎模型中研究Roseotoxin B的免疫抑制活性。在第一章中,我们对接触性皮炎和小分子环肽Roseotoxin B目前的研究进展进行综述介绍,阐述了目前接触性皮炎发病的影响因素、致病机理、调控因素以及常用药物,同时也揭示了Roseotoxin B治疗免疫性疾病的潜质。在第二章中,我们构建动物模型考察Roseotoxin B对PC1诱导的接触性皮炎的治疗作用。实验结果发现,给予RoseotoxinB的小鼠能明显缓解耳组织病理变化及耳部厚度,改善接触性皮炎的发病程度。之后,我们利用细胞学实验考察了RoseotoxinB对T淋巴细胞的影响。实验结果显示,RoseotoxinB不影响T细胞的活化,但是能显著抑制活化T细胞的增殖、炎症因子的释放,并且能够造成活化T细胞的周期阻滞。以上结果提示环肽Roseotoxin B可显著改善小鼠接触性皮炎模型,其作用与影响T细胞密切相关。在第三章中,我们针对RoseotoxinB改善小鼠接触性皮炎展开分子机制的研究。结果发现,小分子环肽RoseotoxinB可通过上调活化T细胞的自噬水平来降低炎症反应、阻滞细胞周期。最后我们又回归到整体动物水平进行了验证,发现Roseotoxin B改善PCl诱发的小鼠接触性皮炎是依赖于LC3介导的自噬反应的。通过上述研究,我们证明了 RoseotoxinB具有改善PCl诱导的接触性皮炎的作用,揭示了 RoseotoxinB通过上调自噬抑制活化T细胞增殖,发挥免疫抑制活性的药理学新机制。本研究不仅为通过调控自噬改善T细胞介导的免疫性疾病提供了例证,也为临床上接触性皮炎的治疗提供了新的候选药物。
[Abstract]:Allergic contact Dermatitis (ACD) is a delayed hypersensitivity reaction mediated by T cells. Its clinical symptoms include blister, edema and erythema, which are usually treated with cyclosporine A and glucocorticoid. Although these immunosuppressants can effectively regulate the overreaction in the immune process and relieve the symptoms of the disease, the selectivity is poor and adverse reactions often occur. Therefore, it is urgent to search for more selective candidate drugs for over-activated T cells. In previous studies, it was found that the small molecular cyclic peptide RoseotoxinB isolated from the metabolites of Trichothecium roseum fungus. had unique immunosuppressive function. Therefore, we try to study the immunosuppressive activity of Roseotoxin B in mouse contact dermatitis model. In the first chapter, we reviewed the current research progress of contact dermatitis and small molecular cyclic peptide Roseotoxin B, and expounded the influencing factors, pathogenesis, regulatory factors and common drugs of contact dermatitis. It also reveals the potential of Roseotoxin B in the treatment of immune diseases. In chapter 2, we established animal models to investigate the therapeutic effect of Roseotoxin B on PC1 induced contact dermatitis. The results showed that RoseotoxinB could alleviate the pathological changes of ear tissue and the thickness of ear and improve the degree of contact dermatitis. After that, we investigated the effect of RoseotoxinB on T lymphocytes by cytological experiments. The results showed that Roseotoxin B did not affect the activation of T cells, but significantly inhibited the proliferation of activated T cells, the release of inflammatory factors, and caused the cycle arrest of activated T cells. These results suggest that cyclopeptide Roseotoxin B can significantly improve the contact dermatitis model in mice, and its effect is closely related to the influence of T cells. In Chapter 3, we investigate the molecular mechanism of RoseotoxinB in improving contact dermatitis in mice. It was found that small molecular cyclic peptide RoseotoxinB could decrease inflammatory response and block cell cycle by upregulating autophagy of activated T cells. Finally, we returned to the whole animal level to verify that the improvement of Roseotoxin B in PCl induced contact dermatitis in mice was dependent on LC3 mediated autophagy. Through the above studies, we proved that RoseotoxinB can improve the contact dermatitis induced by PCl, and revealed a new pharmacological mechanism of RoseotoxinB inhibiting T cell proliferation through upregulation of autophagy and exerting immunosuppressive activity. This study not only provides an example for the improvement of T cell mediated immune diseases by regulating autophagy, but also provides a new candidate for the treatment of contact dermatitis.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R758.22

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