The TWO Study: A Phase II trial of regulatory T cells in renal transplantation - can we achieve sirolimus monotherapy?

器官移植是一种改变生命的治疗方法，在许多情况下，对于患有终末期器官疾病的患者来说，这是一种挽救生命的治疗方法，但所有患者都需要终生使用强效药物抑制免疫，以防止移植产生排斥反应。免疫抑制药物虽然能有效控制移植排斥反应，但其副作用显著，并增加感染、恶性肿瘤、血管疾病和心脏病的风险。移植医学的一个主要目标是在不降低移植存活的情况下减少对长期药物治疗的需求。在过去的30年里，移植医生和科学家们发现，移植排斥反应是由通常保护我们免受疾病侵害的免疫系统引起的。我们最近发现，免疫系统中也有一些细胞可以控制排异反应。具有这种能力的最重要的细胞是“自然发生的调节性T细胞”或nTreg，在动物研究中获得的大量证据表明，这些细胞可以提供一种无需长期药物治疗的长期移植存活途径。几个研究小组已经证明，这些细胞可以从人体血液中分离出来，并在实验室中培养。重要的是，通过使用一种被称为“人源化小鼠”的特殊类型的小鼠，我们牛津大学首次证明了人类nTreg可以防止人类移植的排斥反应，这为使用人类nTreg来控制移植患者的排斥反应开辟了可能性。我们在牛津跟进了这项工作，参加了一项欧盟资助的临床试验，以确定培养这种细胞的安全性和可行性，并将其用于少数肾移植受者。这项名为“一项研究”的试验几乎已经完成，我们已经证明细胞可以生长，并且可以安全地移植给移植接受者。这项被我们称为“两项研究”的拟议研究是建立在最初的试验基础上的，但这次我们将看看nTreg是否真的能控制排斥反应。我们将在三年内招募34名肾移植受者，每位患者将接受常规免疫抑制药物治疗。然而，在移植后，我们将对患者进行细胞治疗，从他们自己的血液中分离出nTreg，并在伦敦盖伊医院专门建造的细胞设施中培养。然后，我们将减少基于药物的免疫抑制量，并评估肾移植的功能。通过这种方式，我们将寻找这些nTreg在保护移植物免受损害方面发挥作用的证据。我们已经知道，nTreg在预防自身免疫性疾病（如糖尿病和炎症性肠病）方面对我们所有人都至关重要，所以我们非常乐观地认为这些细胞会有一些效果。如果试验成功，那么将有可能考虑在其他领域使用类似的细胞类型，如儿科移植以及心脏、肝脏、肺和肠道移植。这对移植患者有巨大的好处，可以使移植存活更长时间，并有可能降低NHS的移植成本。

Organ transplantation is a life-changing and in many cases, life-saving treatment for patients with end-stage organ disease, but all patients need life-long immunosuppression with powerful drugs to prevent rejection of the transplant. Although effective at controlling transplant rejection, immunosuppressive drugs are associated with significant side-effects and increase the risk of infection, malignancy, vascular disease and heart disease. A primary objective in transplantation medicine is to reduce the need for long-term drug treatment without reducing survival of the transplant. In the past thirty years transplant doctors and scientists have discovered transplant rejection is caused by the immune system that normally protects us from disease. We have more recently discovered that the immune system also contains populations of cells that can actually control rejection. The most important of the cells that have this ability are 'naturally-occurring regulatory T cells' or nTreg, and a large amount of evidence obtained in animal studies has shown that these cells can provide a route to long-term transplant survival without long-term drug treatment. Several research groups have shown that these cells can be isolated from human blood and grown in the laboratory. Importantly, using a special type of mouse called a 'humanised mouse', we in Oxford were the first to show that human nTreg can prevent the rejection of human transplants, which has opened up the possibility that it may be possible to use human nTreg to control rejection in transplant patients.We have followed up this work in Oxford by taking part in an EU-funded clinical trial to determine the safety and feasibility of growing such cells and administering them to a small number of kidney transplant recipients. This trial called The ONE Study, is almost complete and we have shown that cells can be grown and are safe to give to transplant recipients. The proposed study, which we are calling The TWO Study, builds upon the original trial but this time we will look to see if nTreg can actually control rejection. We will recruit 34 kidney transplant recipients over three years and each patient will receive conventional immunosuppressive drugs. However, after transplant, we will give to the patient a cellular therapy of nTreg isolated from their own blood and grown in a purpose-built cell facility at Guy's Hospital in London. Then, we will reduce the amount of drug-based immunosuppression and assess the function of the kidney transplants. In this way, we will look for evidence that these nTreg can play a role in protecting the transplants from damage. We already know that nTreg are vitally important in all of us for preventing autoimmune diseases such as diabetes and inflammatory bowel disease so we are very optimistic that these cells will have some effect. If the trial is successful, it will then be possible to think about using similar cell types in other areas such as paediatric transplants as well as heart, liver, lung and intestinal transplantation. This could have a huge benefit to transplant patients by making transplant survive for longer and potentially could reduce the costs of transplantation to the NHS.