Understanding T cell immunity in anti-NMDAR encephalitis: Developing therapeutic tools for neurological autoimmunity.

脑炎(脑部发炎)每年影响英国6000人。它通常会导致严重的残疾，包括癫痫发作、记忆问题、丧失独立性和失业，所有这些都会影响患者的家人和照顾者。虽然许多病例是由感染引起的，但大量病例是由于免疫反应异常造成的，即免疫系统的细胞产生抗体，攻击健康脑细胞表面的特定蛋白质。目前，虽然我们有一些免疫介导性脑炎的治疗方法，但患者往往对治疗产生抵触，反应不佳，需要在专科病房或重症监护病房住院数月。迫切需要了解免疫介导性脑炎是如何和为什么发生的，并确定新的治疗形式，以改善我们患者的康复和预后。目前尚不清楚是什么触发了导致脑炎的自身抗体的产生，但最近的证据表明，一种特定类型的免疫细胞(T细胞)在其产生中发挥了重要作用。此外，最近还观察到，一些新的癌症治疗方法被称为“检查点抑制物”，或者更笼统地说，是“癌症免疫疗法”，它们通过影响T细胞功能来发挥作用，可能会导致免疫介导性脑炎和其他免疫介导性神经并发症。这些检查点抑制剂使正常的T细胞更具侵略性地攻击癌细胞，但不幸的是，作为副作用，未受调控的T细胞可能会导致自身免疫，还会损害健康的身体细胞，包括大脑中的细胞。拟议的项目有两个广泛的目标：(I)描述免疫介导性脑炎和接受检查点抑制剂治疗后出现神经并发症的患者的T细胞反应的功能；(Ii)利用最先进的基因工程技术，通过产生调节性免疫细胞(Treg)来开发有针对性的免疫抑制疗法，这种细胞可以在大脑中被激活，以抑制炎症，无论其原因是什么。对于第一个目的，我们将检测健康志愿者和患者的T细胞的数量和功能，并研究在患有脑炎和NMDAR自身抗体的患者中，是否更容易触发不需要的T细胞对特定脑蛋白(NMDAR多肽)的反应。第二个目的，我们将探索基因工程T细胞在免疫介导性脑炎治疗中的应用。虽然有些T细胞具有“攻击”功能，如致病T细胞，但其他T细胞(调节性T细胞，或Tregs)是免疫调节器，可以抑制炎症。我们将使用最先进的基因工程来产生T调节器，这种调节器可以在进入大脑时被激活，并关闭异常炎症。设计一种个性化的、精确靶向的脑炎细胞疗法，不仅可以改变我们治疗脑炎的方式，还可以改变我们治疗一系列其他大脑炎症性疾病的方式，比如多发性硬化症。在过去的15年里，伦敦大学学院一直站在T细胞工程的前沿，现在拥有欧洲最大的基因工程免疫细胞临床转化管道。最近，基因工程T细胞已经被引入作为一种治疗儿童白血病的许可疗法。在大脑中，他们也在胶质母细胞瘤患者身上进行试验，胶质母细胞瘤是脑瘤的一种。我们的目标是在实验室完成这些细胞的临床前测试。如果成功，这可能为未来3-5年内的I期临床试验铺平道路。

Encephalitis (inflammation of the brain) affects 6000 people in the UK annually. It commonly causes significant disability, including seizures, memory problems, loss of independence and unemployment all of which affect families and carers of patients. While many cases are caused by infection, a large number occur as a result of abnormal immune responses, where cells of the immune system produce antibodies, which attack specific proteins on the surface of healthy brain cells. Currently, while we have some available treatments for immune-mediated encephalitis, often patients are resistant to treatment, respond poorly and need to remain in hospital for several months either on a specialist ward or the intensive care unit. There is a pressing need to understand how and why immune-mediated encephalitis occurs, and to identify new forms of treatment to improve recovery and outcomes for our patients. It is not known what triggers the generation of autoantibodies that cause encephalitis, but recent evidence has suggested an important role for a specific type of immune cell (T cells) in their generation. In addition, it has recently been observed that some new cancer treatments called 'checkpoint inhibitors' or more generally, 'cancer immunotherapy', which work by affecting T cell function, can cause immune-mediated encephalitis and other immune-mediated neurological complications. These checkpoint inhibitors make normal T cells attack cancer cells more aggressively, but unfortunately, as a side effect, unregulated T cells can cause autoimmunity and also damage healthy body cells including cells in the brain. The proposed project has 2 broad aims: (i) to characterise the function of T cell responses in patients with immune mediated encephalitis and with neurological complications after checkpoint inhibitor therapy; and (ii) to use state of the art genetic engineering to develop targeted immune suppressive therapies by generating regulatory immune cells (Tregs), which can be activated within the brain to suppress inflammation regardless of it's cause. For the first aim we will examine the number and function of T cells in healthy volunteers and in patients and investigate whether it is easier to trigger unwanted T cell responses to specific brain proteins (NMDAR peptides) in patients who develop encephalitis and NMDAR autoantibodies.For the second aim we will explore the use of gene-engineered T cells in the treatment of immune-mediated encephalitis. While some T cells have an 'attack' function, such as those causing disease, others (Regulatory T cells, or Tregs) are immune regulators and can suppress inflammation. We will use state-of-the-art genetic engineering to generate T regs which can become activated on entry into the brain, and switch off abnormal inflammation. Designing a personalised, precision-targeted cellular therapy for encephalitis, could transform the way we think about treating not just encephalitis, but a range of other inflammatory diseases of the brain, such as multiple sclerosis.Over the last 15 years, University College London has been at the forefront of T cell engineering and now has the largest clinical translation pipeline of genetically engineered immune cells in Europe. Recently gene-engineered T cells have been introduced as a licensed treatment for childhood leukaemias. In the brain, they are also being trialled in patients with glioblastoma, a type of brain tumour. We aim to complete pre-clinical testing of these cells in the laboratory. If successful this could pave the way for a phase I clinical trials in the next 3-5 years.