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

器官移植对于终末期器官疾病患者来说是一种改变生命的治疗，在许多情况下是挽救生命的治疗，但所有患者都需要终生免疫抑制，并使用强大的药物来防止移植排斥反应。虽然免疫抑制药物在控制移植排斥反应方面有效，但它也有明显的副作用，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物存活率的情况下减少对长期药物治疗的需求。在过去的30年里，移植医生和科学家发现，移植排斥反应是由通常保护我们免受疾病侵袭的免疫系统引起的。我们最近发现，免疫系统中也含有能够实际控制排斥反应的细胞群。具有这种能力的细胞中最重要的是自然产生的调节性T细胞或nTreg，动物研究中获得的大量证据表明，这些细胞可以为移植后的长期存活提供一条途径，而不需要长期的药物治疗。几个研究小组已经证明，这些细胞可以从人类血液中分离出来，并在实验室中培养。重要的是，我们牛津大学第一个证明人类nTreg可以防止人体移植排斥反应的老鼠是一种特殊类型的老鼠，这为利用人类nTreg控制移植患者的排斥反应打开了可能性。我们在牛津继续这项工作，参与了一项由欧盟资助的临床试验，以确定培养这种细胞并将其应用于少数肾移植受者的安全性和可行性。这项名为One Study的试验已接近完成，我们已经证明细胞可以生长，可以安全地提供给移植接受者。这项拟议的研究，我们称之为两项研究，建立在最初的试验基础上，但这一次我们将看看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，每个患者都将接受传统的免疫抑制药物。然而，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生长。然后，我们将减少药物免疫抑制的量，并评估肾移植的功能。通过这种方式，我们将寻找证据表明这些nTreg可以在保护移植物免受损害方面发挥作用。我们已经知道，nTreg对于预防糖尿病和炎症性肠病等自身免疫性疾病至关重要，因此我们非常乐观地认为，这些细胞将产生一些效果。如果试验成功，那么就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。这可能会使移植患者存活更长时间，从而为移植患者带来巨大的好处，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.