Applying advanced understanding of CTLA-4 function to optimise therapies for autoimmunity

应用对 CTLA-4 功能的深入理解来优化自身免疫疗法

• 批准号: MR/Y001273/1
• 负责人: Lucy Walker
• 金额: $ 255.11万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY001273%2F1
• 关键词: Applying; advanced; understanding; CTLA; function

While the immune system protects us from infection by viruses and bacteria, the weapons used to destroy such pathogens can also attack our own bodies resulting in autoimmune diseases. Collectively, these diseases are relatively common and include type 1 diabetes, rheumatoid arthritis and multiple sclerosis along with numerous other conditions. Genetic evidence suggests that these diseases are regulated by common pathways.We are trying to understand how a key mechanism, involving a protein called CTLA-4, works to control the immune system. People with a faulty CTLA-4 gene have poorly controlled immune systems and can develop multiple autoimmune diseases. However, our understanding of exactly what CTLA-4 does is still limited. In this proposal we will increase our knowledge of how CTLA-4 works and test ways to improve its function so we can develop better treatments for autoimmune diseases.CTLA-4 works together with 3 other molecules (CD28, CD80, CD86) that are expressed on cells of the immune system, forming a type of thermostat for controlling immune activity. Preventing CTLA-4 function "turns up" the immune response and has generated a major breakthrough in cancer therapy, where the immune system can be used to attack cancer. However, the side effects of this treatment are autoimmune responses that can damage the body. We wish to develop a better understanding of how we might enhance CTLA-4 function and "turn down" the immune response to treat autoimmune conditions.Both CD28 and CTLA-4 are expressed on T cells, specialised white blood cells that play a key role in triggering immune responses. CD28 promotes T cell activation and without it immune responses are feeble. On the other hand, CTLA-4 regulates T cell responses, to prevent them getting out of hand. A precise understanding of how CTLA-4 works with its partners would enable us to change the strength of immune responses as desired, for example increasing immune responses against tumours or decreasing unwanted immune responses in autoimmune conditions. The challenge we face is that the pathway is complex. Although CD28 and CTLA-4 have opposing functions, they share the same binding partners, CD80 and CD86. In our previous work we found that CTLA-4 behaves in an unusual way, essentially "eating" CD80 and CD86 so they cannot promote immune responses via CD28. This "eating" behaviour has been difficult to study, but with previous funding we have now generated novel research tools that allow us to visualise it in a different way. These tools will be used in the present proposal to allow us to see for the first time how CTLA-4 captures its ligands at different places in the body, both under normal conditions and during the course of an autoimmune disease.We have also discovered key differences in how the two binding partners, CD80 and CD86, affect CTLA-4 behaviour during the "eating" process. We now plan to use this understanding to test ways to improve CTLA-4 function and enhance immune suppression. We will also investigate how the upregulation of CD86 and CD80 is controlled, looking at how cells communicate between each other to collectively reach a decision. This cooperation between cells may affect CTLA-4 function and could explain why regulation sometimes fails. Lastly, soluble CTLA-4 (abatacept) is used clinically in rheumatoid arthritis but performs rather poorly in other autoimmune diseases. Our work has generated new ideas on how to overcome this limitation and we will test these with the goal of generating more effective immune suppression.Overall, this programme will help us to develop better therapies for autoimmune conditions, at a time when these diseases are affecting more and more individuals.

尽管免疫系统可保护我们免受病毒和细菌的感染，但用于销毁此类病原体的武器也可以攻击我们自己的身体，从而导致自身免疫性疾病。总的来说，这些疾病相对常见，包括1型糖尿病，类风湿关节炎和多发性硬化症以及许多其他疾病。遗传证据表明，这些疾病受公共途径调节。我们试图了解涉及称为CTLA-4蛋白质的关键机制如何控制免疫系统。 CTLA-4基因有故障的人的免疫系统控制较差，并且可能患上多种自身免疫性疾病。但是，我们对CTLA-4的确切理解仍然有限。在此提案中，我们将提高人们对CTLA-4如何工作和测试方法改善其功能的了解，以便我们可以为自身免疫性疾病开发更好的治疗方法。CTLA-4与其他3个其他分子（CD28，CD80，CD86）一起工作，这些分子在免疫系统上表达，形成一种用于控制免疫活性的恒温器。防止CTLA-4功能“升高”免疫反应，并在癌症治疗中产生了重大突破，可以使用免疫系统来攻击癌症。但是，这种治疗的副作用是自身免疫反应，可能会损害身体。我们希望更好地了解我们如何增强CTLA-4功能并“降低”以治疗自身免疫性状况的免疫反应。在T细胞上表达了CD28和CTLA-4，这在T细胞上表达，专门的白色血细胞在触发免疫反应中起着关键作用。 CD28促进T细胞激活，没有免疫反应是微弱的。另一方面，CTLA-4调节T细胞反应，以防止它们失控。对CTLA-4如何与其合作伙伴一起工作的精确理解将使我们能够根据需要改变免疫反应的强度，例如增加针对肿瘤的免疫反应或减少自身免疫性条件下不需要的免疫反应。我们面临的挑战是该路径很复杂。尽管CD28和CTLA-4具有相反的功能，但它们共享相同的结合伙伴CD80和CD86。在我们以前的工作中，我们发现CTLA-4的行为以不寻常的方式，本质上是“吃” CD80和CD86，因此它们无法通过CD28促进免疫反应。这种“饮食”行为很难研究，但是借助以前的资金，我们现在已经生成了新颖的研究工具，使我们能够以不同的方式对其进行可视化。这些工具将在本提案中使用，以使我们能够首次查看CTLA-4如何在正常条件下和自身免疫性疾病的情况下在体内的不同地方捕获其配体。我们还发现了两个结合伙伴CD80和CD86的关键差异，CD80和CD86如何影响CTLA-4的饮食过程。现在，我们计划利用这种理解来测试改善CTLA-4功能并增强免疫抑制的方法。我们还将调查如何控制CD86和CD80的上调，以研究细胞之间如何相互交流以集体做出决策。细胞之间的这种合作可能会影响CTLA-4功能，并可以解释为什么调节有时会失败。最后，可溶性CTLA-4（abatacept）在临床上用于类风湿关节炎，但在其他自身免疫性疾病中的性能较差。我们的工作已经产生了有关如何克服这一局限性的新想法，我们将测试这些局限性，以产生更有效的免疫抑制作用。此外，该计划将帮助我们为自身免疫性状况开发更好的疗法，而这些疾病正在影响越来越多的人。