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.

虽然免疫系统保护我们免受病毒和细菌的感染，但用来摧毁这些病原体的武器也会攻击我们自己的身体，导致自身免疫性疾病。总的来说，这些疾病是相对常见的，包括1型糖尿病，类风湿性关节炎和多发性硬化症沿着许多其他条件。遗传学证据表明，这些疾病是由共同的途径调节的。我们正试图了解一种关键机制，涉及一种名为CTLA-4的蛋白质，如何控制免疫系统。CTLA-4基因有缺陷的人免疫系统控制不良，可能会患上多种自身免疫性疾病。然而，我们对CTLA-4的确切作用的了解仍然有限。在这个提案中，我们将增加我们对CTLA-4如何工作的知识，并测试如何改善其功能，以便我们可以开发更好的治疗自身免疫性疾病的方法。CTLA-4与其他3种分子（CD 28，CD 80，CD 86）一起在免疫系统细胞上表达，形成一种控制免疫活性的恒温器。阻止CTLA-4功能“打开”免疫反应，并在癌症治疗中取得了重大突破，其中免疫系统可用于攻击癌症。然而，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如何增强CTLA-4功能并“降低”免疫应答以治疗自身免疫性疾病。CD 28和CTLA-4都表达于T细胞上，T细胞是在触发免疫应答中起关键作用的特化白色血细胞。CD 28促进T细胞活化，没有它，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。精确了解CTLA-4如何与其伙伴一起工作将使我们能够根据需要改变免疫反应的强度，例如增加对肿瘤的免疫反应或减少自身免疫性疾病中不必要的免疫反应。我们面临的挑战是，这条道路是复杂的。虽然CD 28和CTLA-4具有相反的功能，但它们共享相同的结合配偶体CD 80和CD 86。在我们之前的工作中，我们发现CTLA-4以一种不寻常的方式发挥作用，基本上是“吃掉”CD 80和CD 86，因此它们不能通过CD 28促进免疫反应。这种“吃”的行为一直很难研究，但在以前的资助下，我们现在已经产生了新的研究工具，使我们能够以不同的方式可视化它。这些工具将被用于本提案中，使我们能够首次看到CTLA-4如何在正常条件下和自身免疫性疾病过程中在体内不同位置捕获其配体。我们还发现了两种结合伴侣CD 80和CD 86在“进食”过程中如何影响CTLA-4行为的关键差异。我们现在计划利用这种理解来测试改善CTLA-4功能和增强免疫抑制的方法。我们还将研究如何控制CD 86和CD 80的上调，研究细胞如何相互交流以共同做出决定。细胞之间的这种合作可能会影响CTLA-4的功能，并可以解释为什么调控有时会失败。最后，可溶性CTLA-4（阿巴西普）临床上用于类风湿性关节炎，但在其他自身免疫性疾病中表现相当差。我们的工作已经产生了关于如何克服这种限制的新想法，我们将测试这些想法，以产生更有效的免疫抑制。总体而言，这个项目将帮助我们开发更好的治疗自身免疫性疾病的方法，当这些疾病影响越来越多的个体时。