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

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，这些疾病相对常见，包括1型糖尿病、类风湿性关节炎和多发性硬化症以及许多其他疾病。遗传证据表明，这些疾病受到共同途径的调控。我们正试图了解一种关键机制，包括一种名为CTLA-4的蛋白质，是如何控制免疫系统的。CTLA-4基因有缺陷的人免疫系统控制不佳，可能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。在这个提议中，我们将增加我们对CTLA-4如何工作的了解，并测试改善其功能的方法，以便我们能够开发出更好的自身免疫性疾病治疗方法。CTLA-4与另外3种在免疫系统细胞上表达的分子（CD28、CD80、CD86）一起工作，形成一种控制免疫活性的恒温器。阻止CTLA-4的功能“打开”免疫反应，并在癌症治疗中产生了重大突破，免疫系统可以用来攻击癌症。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“抑制”免疫反应来治疗自身免疫性疾病。CD28和CTLA-4都在T细胞上表达，T细胞是一种特殊的白细胞，在触发免疫反应中起着关键作用。CD28促进T细胞活化，没有它免疫反应就很弱。另一方面，CTLA-4调节T细胞反应，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疾病中不必要的免疫反应。我们面临的挑战是，途径是复杂的。虽然CD28和CTLA-4具有相反的功能，但它们具有相同的结合伙伴CD80和CD86。在我们之前的工作中，我们发现CTLA-4以一种不寻常的方式表现，本质上是“吃掉”CD80和CD86，因此它们不能通过CD28促进免疫反应。这种“进食”行为一直很难研究，但在之前的资助下，我们现在已经开发出了新的研究工具，使我们能够以不同的方式将其可视化。这些工具将在本提案中使用，使我们能够首次看到CTLA-4在正常情况下和自身免疫性疾病过程中如何在体内不同部位捕获其配体。我们还发现了两个结合伙伴CD80和CD86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一认识来测试改善CTLA-4功能和增强免疫抑制的方法。我们还将研究CD86和CD80的上调是如何被控制的，并观察细胞之间如何相互沟通以共同做出决定。细胞之间的这种合作可能会影响CTLA-4的功能，并可以解释为什么有时调节失败。最后，可溶性CTLA-4 （abataccept）在临床上用于类风湿性关节炎，但在其他自身免疫性疾病中的表现相当差。我们的工作产生了关于如何克服这一限制的新想法，我们将测试这些想法，以产生更有效的免疫抑制。总的来说，这一方案将帮助我们开发更好的自身免疫性疾病治疗方法，目前这些疾病正在影响越来越多的人。

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.