New approaches to better understand an old treatment regimen - molecular, cellular and live intravital imaging studies on glucocorticoid therapy of experimental autoimmune encephalomyelitis as a model of multiple sclerosis

更好地理解旧治疗方案的新方法 - 作为多发性硬化症模型的实验性自身免疫性脑脊髓炎糖皮质激素治疗的分子、细胞和活体活体成像研究

• 批准号: 193379304
• 负责人: Privatdozent Dr. Fred Lühder
• 金额: --
• 依托单位: Institut für Zelluläre und Molekulare Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/193379304?language=en
• 关键词: New; approaches; better; understand; old

Treatment of acute relapses with glucocorticoids (GCs) is a mainstay in multiple sclerosis (MS) therapy. Induction of T cell apoptosis is currently believed to be one of the central mechanisms of this regimen but our recent findings challenge this view. GCs ameliorate experimental autoimmune encephalomyelitis (EAE) in mice that are refractory to apoptosis, raising the question as to which mechanisms are then responsible for therapeutic success. Preliminary in vitro data point towards a profound effect of GCs on leukocyte motility. By combining genetically modified mice not previously investigated in this context with molecular and immunological analyses and new techniques such as intravital 2-photon laser scanning microscopy we will determine the influence of GC treatment on the locomotion of immune cells directly within the lymphatic organs and the CNS of living mice. In parallel, we will investigate the role of well-established and potentially new GC actions on cytokine production, T cell priming, transmigration, morphology and the formation of the immunological synapse. Lastly, we plan to initiate first experiments to validate our findings using human T cells. In summary, the combination of new mouse models with molecular analyses and state-of-the-art imaging techniques should place us in a position to address crucial aspects of GC action such as the importance of apoptosis induction, leukocyte motility and trafficking as well as T cell reactivation.

用糖皮质激素（GC）治疗急性复发是多发性硬化（MS）治疗的主要手段。目前认为诱导T细胞凋亡是该方案的核心机制之一，但我们最近的研究结果挑战了这一观点。GC改善了小鼠的实验性自身免疫性脑脊髓炎（EAE），这是细胞凋亡难治性的，提出了一个问题，即哪些机制是治疗成功的原因。初步的体外数据表明GC对白细胞运动有深远的影响。通过结合基因修饰小鼠以前没有在这种情况下，分子和免疫学分析和新技术，如活体2-光子激光扫描显微镜，我们将确定GC治疗的免疫细胞的运动直接在淋巴器官和中枢神经系统的活小鼠的影响。与此同时，我们将研究成熟的和潜在的新的GC对细胞因子产生，T细胞引发，迁移，形态和免疫突触形成的作用。最后，我们计划启动第一个实验，使用人类T细胞验证我们的发现。总之，新的小鼠模型与分子分析和国家的最先进的成像技术相结合，应该把我们的位置，以解决关键方面的GC行动，如细胞凋亡诱导，白细胞运动和贩运以及T细胞活化的重要性。