A mechanistic evaluation of gliflozins in CD4+ T cells and their repurposing in T cell-mediated autoimmunity

过度活跃的免疫系统是自身免疫性疾病的原因，如风湿性关节炎和系统性红斑狼疮（狼疮）。自身免疫是指身体自身的免疫细胞，称为t细胞，攻击健康的组织和器官。大多数自身免疫性疾病无法治愈，目前的治疗方法并不总是有效，导致许多患者出现虚弱的症状，严重限制了他们的生活质量。在这个提议中，我们将研究一组被称为格列净的药物是否可以用于治疗自身免疫性疾病。格列净是一种安全且经临床批准的药物，目前用于治疗2型糖尿病，因为它们可以控制血糖水平。一些格列净还有额外的作用，破坏我们的细胞从饮食中代谢能量（如糖和蛋白质）的方式。自身免疫t细胞调整它们的新陈代谢——它们吸收和处理糖和蛋白质的方式，这有助于它们攻击身体的健康组织和器官。通过影响我们的t细胞处理营养物质的方式，我们推断某些格列净可以作为自身免疫的治疗方法。我们将分三个阶段进行这项研究——首先使用健康供体血液中的t细胞，其次在类风湿性关节炎和狼疮患者的t细胞上测试药物，最后观察药物在自身免疫小鼠模型中的作用。如果这项研究证实了我们的想法，这些结果将为格列净治疗自身免疫的临床试验的设计提供信息，目的是改善自身免疫患者的预后。由于格列净已经被安全地用于其他目的，这些益处可能会相对较快地到达患者身上。这项研究将在斯旺西大学医学院进行，那里的人类免疫细胞专家将与布里斯托尔大学、弗朗西斯克里克研究所和伦敦大学学院的科学家合作。我们将在实验室中通过测试多种自身免疫性疾病（类风湿性关节炎和狼疮）中暴露于格列净的t细胞的代谢和功能来完成这项工作。我们的最终目标是通过更好地了解格列净如何影响t细胞活性，特别是通过确定不同类型格列净的作用，使自身免疫性疾病患者的治疗方法得到改进。

An overactive immune system is the cause of autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus (lupus). Autoimmunity is where the body's own immune cells, called T-cells, attack healthy tissues and organs. Most autoimmune conditions have no cure and current therapies are not always effective, leaving many patients with debilitating symptoms that severely restrict their quality of life. In this proposal, we will examine whether a group of drugs called gliflozins could be used to treat autoimmune diseases. Gliflozins are a safe and clinically approved drug class currently used to treat type 2 diabetes because they control blood-sugar levels. Some gliflozins have additional effects and disrupt the way our cells metabolise fuels from our diet such as sugar and protein. Autoimmune T-cells adapt their metabolism - the way in which they take up and process sugar and protein and this helps them attack the body's healthy tissues and organs.By affecting the ways in which our T-cells process nutrients, we reason that certain gliflozins could work as a treatment for autoimmunity. We will carry out this research in three stages - first by using T-cells from healthy donors' blood, secondly by testing the drugs on T-cells obtained from rheumatoid arthritis and lupus patients amongst others, and finally seeing how the drugs work in a mouse model of autoimmunity. If this research confirms our thinking, these results will inform the design of a clinical trial of gliflozins for treatment of autoimmunity, with the goal of improving outcomes in people with autoimmunity. Since gliflozins are already prescribed safely for other purposes, these benefits could potentially reach patients relatively rapidly. The research will be carried out at Swansea University Medical School, where specialists in human immune cells will collaborate with scientists at the University of Bristol, the Francis Crick Institute and University College London. We will do this work in the laboratory by testing the metabolism and function of T-cells exposed to gliflozins in multiple autoimmune diseases (rheumatoid arthritis and lupus).Our ultimate aim is to enable the development of improved treatments for people with autoimmune disorders by better understanding how gliflozins might affect T-cell activity, and in particular by determining the effects of different types of gliflozins.