REsolving Seronegative and CheckpOint inhibitor-induced iNflammatory ArthriTis by synovial dEconstruction (RESONATE)

通过滑膜解构 (RESONATE) 解决血清阴性和检查点抑制剂诱导的炎症性关节炎

• 批准号: MR/X02914X/1
• 负责人: Arthur Pratt
• 金额: $ 72.4万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX02914X%2F1
• 关键词: REsolving; Seronegative; CheckpOint; inhibitor; induced

The immune system is highly effective at protecting us from harmful infection. It also helps prevent cancer by recognising and destroying cancer cells. As the immune system ages, however, it can itself cause disease which, when it affects the joints, is referred to as inflammatory arthritis. For those with rheumatoid arthritis whose blood tests are positive for markers called autoantibodies (seropositive RA), or those with an easily recognisable skin rash (psoriatic arthritis, PsA), it may be relatively simple for doctors to diagnose and treat these conditions. Indeed, the outlook for such patients has improved markedly thanks to a better understanding of underlying disease processes and the availability of drugs that target them. However, up to 500,000 UK adults suffer from other forms of "seronegative" inflammatory arthritis (SIA - so-called because their autoantibody tests are negative). These patients typically experience a long-term condition characterised by stiff, swollen joints, which is often disabling. Our understanding of SIA and how to treat it lags behind seropositive RA and PsA.The development of a new class of drugs in cancer medicine, called immune checkpoint inhibitors (CPIs) could help us understand this problem in a new way. CPIs work by helping the immune system to attack and kill cancer cells, transforming the outlook for a rapidly increasing number of cancer patients. However, this strategy can also unleash the immune system on the body's harmless cells, and some CPI-treated patients develop inflammatory arthritis as a 'side effect.' In general, "CPI-induced arthritis" (CPIA) is remarkable for its similarity to SIA - and is just as difficult to manage. It affects around 8% of adults prescribed CPI therapy. We propose that by understanding this overlap between CPIA (precipitated by a known intervention) and SIA (whose cause is unknown) we will be able to find new ways to treat these diseases, either by repurposing treatments already used in other diseases or by identifying completely new approaches. Researchers in Newcastle and Birmingham have worked together to collect and store blood and samples of joint lining (the synovium) from people with different forms of immune mediated inflammatory arthritis. Using samples from patients with SIA, CPIA, seropositive RA and PsA, we will employ recently developed technologies to extract highly detailed information about constituent cells in each condition, and how they interact with one another to drive inflammatory disease. Using computational approaches to compare them in collaboration with colleagues at the University of Glasgow and GSK, we will seek to identify the particular pathological features of SIA that explain why it looks so similar to CPI-induced arthritis in the clinic. The information gained should (i) help identify future treatment approaches for both conditions and (ii) help us develop blood tests to predict those individuals most likely to benefit from them. As a preliminary test of such treatments, we will explore their ability to disrupt the unwanted behavior of implicated disease-causing cells in the laboratory. In parallel, we will work with our network of academic and pharmaceutical collaborators to design trials that test them in the clinic

免疫系统在保护我们免受有害感染方面非常有效。它还有助于通过识别和破坏癌细胞来预防癌症。然而，随着免疫系统的老化，它本身也会引起疾病，当它影响关节时，被称为炎症性关节炎。对于那些患有类风湿性关节炎的人，他们的血液测试对称为自身抗体（血清阳性RA）的标记物呈阳性，或者那些容易识别的皮疹（银屑病关节炎，PsA），医生诊断和治疗这些疾病可能相对简单。事实上，由于对潜在疾病过程的更好理解以及针对这些疾病的药物的可用性，这些患者的前景已经明显改善。然而，多达50万英国成年人患有其他形式的“血清阴性”炎性关节炎（SIA -所谓的，因为他们的自身抗体测试是阴性的）。这些患者通常会经历一个长期的条件，其特征是僵硬，肿胀的关节，这往往是致残。我们对SIA及其治疗方法的理解落后于血清阳性RA和PsA。癌症医学中一类新药物的开发，称为免疫检查点抑制剂（CPI），可以帮助我们以新的方式理解这个问题。CPI通过帮助免疫系统攻击和杀死癌细胞来发挥作用，改变了迅速增加的癌症患者的前景。然而，这种策略也可以释放免疫系统对身体的无害细胞，一些CPI治疗的患者发展为炎症性关节炎作为一种“副作用”。一般来说，“CPI诱导的关节炎”（CPIA）与SIA的相似性是值得注意的，而且同样难以管理。它影响了约8%的CPI治疗处方的成年人。我们建议，通过了解CPIA（由已知干预引起）和SIA（其原因未知）之间的这种重叠，我们将能够找到治疗这些疾病的新方法，无论是通过重新利用已用于其他疾病的治疗方法，还是通过确定全新的方法。纽卡斯尔和伯明翰的研究人员合作收集和储存血液和关节衬里（滑膜）样本，这些样本来自不同形式的免疫介导的炎症性关节炎患者。使用来自SIA，CPIA，血清阳性RA和PsA患者的样本，我们将采用最近开发的技术来提取有关每种疾病中组成细胞的高度详细信息，以及它们如何相互作用以驱动炎症性疾病。与格拉斯哥大学和GSK的同事合作，使用计算方法比较它们，我们将寻求确定SIA的特殊病理特征，解释为什么它在临床上看起来如此类似于CPI诱导的关节炎。所获得的信息应该（i）帮助确定这两种疾病的未来治疗方法，（ii）帮助我们开发血液测试，以预测最有可能从中受益的人。作为这种治疗的初步测试，我们将探索它们在实验室中破坏相关致病细胞的不必要行为的能力。与此同时，我们将与我们的学术和制药合作者网络合作，设计在临床上进行测试的试验