MICA: Regulatory T cells in Highly Sensitised Renal Patients to Improve Outcomes after HLA-Ab Incompatible Transplantation

肾移植是治疗肾衰竭的最佳方法。供体器官的分配使用各种标准，其中之一是针对组织抗原HLA的抗体（Ab）的存在，这表明潜在的受体是否会对特定的供体产生积极的排斥反应。如果任何一种Ab抗体对潜在的捐献者产生反应，则不会提供器官。有多种抗体的透析患者，占移植名单的三分之一，因此可以等待很长时间才能找到合适的供体。在我们的中心，我们提供专门的治疗，使Ab在分配过程中被忽略。这包括使用更强效的药物来抑制免疫系统。通过这种方式移植的患者存活的时间和他们选择透析换另一个器官的时间一样长，但仍然有很高的排异率，而且更多的移植在最初几年失败，因为移植器官对HLA的反应更激烈。因此，这种方法是为迫切需要移植的患者保留的，很少有其他中心提供这种方法。我们需要一种新的方法来改善这组患有多种Ab的患者的治疗效果。这项研究将测试一种新的个性化方法，使用患者自身具有天然抑制特性的特殊白细胞（称为“调节性T细胞”（Tregs）），我们将在实验室中对其进行纯化和培养，然后再将其注入体内。我们对现有移植患者的经验表明，treg在某些方面是缺乏的，但当它们存在时，它们可以抑制对HLA的侵袭性反应。我们还从几名肾衰竭患者身上取出并扩增treg，并在移植后不久安全地将它们放回，包括我们在这里使用的细胞剂量。对于这个应用，我们想要证明我们可以在移植前测量treg对特定HLA反应的抑制作用。首先，我们将研究这些患者对HLA的反应方式，使用实验室测试，使我们能够确定treg是否存在并能够抑制反应。为了超越这一点，我们需要在至少21名患者中看到一种特定的反应模式，但我们会招募更多的患者来考虑那些想要退出或接受移植的患者。我们会将这些病人随机分为两组。第一组12人将立即接受Tregs治疗。第二组9人将获得延迟的treg，在他们等待的同时，我们将使用不同的免疫测试来监测他们，试图了解我们的测量值如何随时间变化并自发变化，这些信息以前没有人收集过，但这对我们能够定义treg的特定效果至关重要。为了产生用于治疗的treg，新兵将接受类似透析的治疗，从血液中分离出大量白细胞，我们将从血液中分离出treg，在实验室中培养，几周后，我们将以单次剂量重新注入它们。然后，我们将描述与对照相同的免疫监测测量，以确定我们的治疗是否改变了对HLA的抑制反应，并改变了treg的数量和亚型。我们设计试验的目的是，在治疗第一组12名患者后，如果Treg似乎效果甚微，我们可以停止试验，但如果Treg似乎起作用，我们可以继续治疗第二组，这样我们就可以更好地确定抑制HLA反应的比例和Treg效果的持续时间。这项研究将告知是否有可能进行更大规模的试验，该试验需要包括接受移植的患者。如果是这样，我们希望我们可以说服其他中心参与进来。最终，我们希望证明这些treg能够安全地降低排异率，防止移植失败，从而帮助更多这些高度弱势的患者接受移植。

Kidney transplantation is the best treatment for patients with kidney failure. Donor organs are allocated using various criteria, one of which is the presence of antibodies (Ab) against tissue antigens called HLA, which indicate whether potential recipients will mount an aggressive rejection response against a particular donor. Organs are not offered if any of the Ab react against a prospective donor. Dialysis patients with multiple Abs, who account for up to 1/3rd on the transplant list, can therefore wait a long time for a suitable donor. In our centre, we offer specialised treatment which allows Ab to be ignored by the allocation process. This involves use of more powerful drugs to suppress the immune system. Patients transplanted this way survive for as long as if they had chosen to wait on dialysis for a different organ, but still suffer high rates of rejection, and more of their transplants fail in the first few years, because of the more aggressive responses against HLA on the organ. Consequently, this approach is reserved for patients who need a transplant urgently and is offered by few other centres. A new approach is needed to improve outcomes for this group with multiple Ab. This study will test a new personalised approach, using the patient's own specialised white blood cells with natural suppressive properties (called 'regulatory T cells' (Tregs)) that we will purify and grow-up in the laboratory before infusing them back. Our experience in patients with existing transplants suggests that Tregs are deficient in some, but when present, they can suppress aggressive responses to HLA. We have also taken out and expanded Tregs from several patients with kidney failure and given them back safely, shortly after transplantation, including the dose of cells we will use here. For this application we want to show that we can measure a suppressive effect of Tregs on responses to specific HLA before transplantation. First, we will study the way that these patients respond to HLA, using lab tests that allow us to define whether Tregs are present and capable of suppressing the response. To continue beyond this point, we need to see a specific pattern of response in least 21 patients, but will recruit a few more to account for patients who want to drop out or who get offered a transplant. We will ask these patients to be randomly allocated to one of two groups. The first group of 12 will be administered Tregs immediately. The second group of 9 will get delayed Tregs, and whilst they are waiting, we will monitor them using our different immune tests, to try and understand how our measurements change with time and vary spontaneously, information that no-one has ever gathered before, but which is vital for us to be able to define a specific effect of Tregs. To generate the Tregs for treatment, recruits will undergo a dialysis-like treatment to isolate a large number of white cells from blood, from which we will isolate the Tregs, grow up in the lab, before we re-infuse them, in a single dose, a few weeks later. We will then describe the same immune monitoring measurements with reference to the controls, to determine whether our treatment changes the suppression of responses to HLA and changes the numbers and subtypes of Tregs. We have designed the trial so that we can stop the trial after treating the first group of 12 if Tregs appear to have minimal effect, but continue with treating the second group if Tregs appear to work, so that we can better define both the proportion showing suppression of HLA responses and the duration of the Treg effect. This study will inform whether a larger trial, which will need to include patients being transplanted, is feasible. If so, we hope we can then persuade other centres to get involved. Ultimately, we want to demonstrate that these Tregs will safely reduce rejection rates and prevent transplant failure, thereby helping more of these highly disadvantaged patients to get transplanted.