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

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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.