Can regulatory T cells improve outcomes of sensitised patients after HLA-Ab incompatible renal transplantation: study protocol for the Phase IIa GAMECHANgER-1 trial.

BACKGROUND: Kidney transplantation is the gold-standard treatment for patients with kidney failure. However, one-third of patients awaiting a kidney transplant are highly sensitized to human leukocyte antigens (HLA), resulting in an increased waiting time for a suitable kidney, more acute and chronic rejection, and a shorter graft survival compared to non-highly sensitised patients. Current standard immunosuppression protocols do not adequately suppress memory responses, and so alternative strategies are needed. Autologous polyclonally expanded regulatory T cells (Tregs) have been demonstrated to be safe in transplant settings and could be a potential alternative to modulate memory immune alloresponses. METHODS: The aim of this trial is to determine whether adoptive transfer of autologous Tregs into HLA sensitised patients can suppress memory T and B cell responses against specific HLA antigens. This is a two-part, multi-centre, prospective clinical trial, comprising an observational phase (Part 1) aiming to identify patients with unregulated cellular memory responses to HLA (Pure HLA Proteins) followed by an interventional phase (Part 2). The first 9 patients identified as being eligible in Part 1 will undergo baseline immune monitoring for 2 months to inform statistical analysis of the primary endpoint. Part 2 is an adaptive, open labelled trial based on Simon's two-stage design, with 21 patients receiving Good Manufacturing Practice (GMP)-grade polyclonally expanded Tregs to a dose of 5-10 × 106 cells/kg body weight. The primary EP is suppression of in vitro memory responses for 2 months post-infusion. 12 patients will receive treatment in stage 1 of Part 2, and 9 patients will receive treatment in stage 2 of Part 2 if ≥ 50% patients pass the primary EP in stage 1. DISCUSSION: This is a prospective study aiming to identify patients with unregulated cellular memory responses to Pure HLA Proteins and determine baseline variation in these patterns of response. Part 2 will be an adaptive phase IIa clinical trial with 21 patients receiving a single infusion of GMP-grade polyclonally expanded Tregs in two stages. It remains to be demonstrated that modulating memory alloresponses clinically using Treg therapy is achievable. TRIAL REGISTRATION: EudraCT Number: 2021-001,664-23. REC Number: 21/SC/0253. Trial registration number ISRCTN14582152.

Modern renal transplantation: present challenges and future prospects.

Renal transplantation offers patients with end stage renal failure improved survival and quality of life compared with dialysis. Although more transplants are being performed in the UK and elsewhere, the size of the renal transplant waiting list is increasing at a faster rate. Live donor transplantation between antibody compatible and incompatible pairs is one of the short term solutions to this; it may also be a sensible long term strategy since it affords better outcomes. Following successful transplantation, balancing the chronic and often deleterious effects of immunosuppression with chronic immune damage poses the key clinical challenge for transplant physicians today. Research efforts worldwide are focused towards immunological tolerance of transplanted organs with two main questions: first, how can we induce tolerance; and second, how can we test that it is operational? Immunosuppressive protocols vary greatly between transplant units, which may be reflected in differing patient and allograft survival.

Changing practice to improve pain control for renal patients.

Pain is a common symptom described by patients with end-stage kidney disease (ESKD) but remains ineffectively managed. The aim of this audit was to determine what proportion of these patients report pain, then introduce the use of an analgesic ladder adapted specifically for ESKD, and finally re-evaluate the prevalence of pain symptoms, looking for an improvement. A cohort of inpatients on the renal wards of a West London teaching hospital was studied. The number of patients reporting pain and the severity of their pain on a scale of 1-10 were recorded. A considerable number of patients were barred from participating because of a language barrier. Interpreters were introduced, and the phase was repeated. The World Health Organization (WHO) three-step analgesic ladder was adapted for patients with ESKD and introduced to medical staff on the renal wards. The number of patients reporting pain and the severity of their pain were re-recorded. There was a significant reduction in the number of patients reporting pain and the severity of their pain. Pain control in patients with ESKD is improved through the use of an adapted version of the WHO analgesic ladder. Strategies must be in place for effective communication with foreign patients.

Rejection mechanisms in transplantation.

While major improvements have been made in the prevention and treatment of hyperacute and acute transplant rejection, most grafts will succumb to chronic rejection: this reflects the extent of our knowledge of the mechanisms that drive these processes. Clinically, transplant rejection is classified according to timeframe and histology into hyperacute (minutes to hours), acute (days to months) and chronic rejection (months to years). Hyperacute and acute rejection are reasonably well understood and occur by immune mediated events whereas chronic rejection probably has immune and non-immune components. The trigger to cell-mediated rejection is allorecognition, where same-species, non-self antigens are detected by the host immune system. This occurs by two distinct mechanisms, called the direct and indirect pathways. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells. Animal and human studies strongly suggest that acute rejection is predominantly triggered by the direct pathway although if the latter is blocked then the indirect pathway can suffice. Donor antigen presenting cells within the graft become depleted with time and the frequency of T cells reactive to the direct pathway diminishes irrespective of whether or not chronic rejection occurs. This implies that the direct pathway is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection although it is unlikely that this is the whole story: there are numerous non-immunological risk factors for chronic rejection which probably interact with immune components causing gradual graft failure. Xenotransplantation, where tissue is transferred across species, causes rejection by processes analogous to those seen in allografts but they are faster and more vigorous. Novel approaches have overcome some early antibody mediated rejection events but then reveal a huge, intense, adaptive cellular response. We believe that by the careful study of the mechanisms of rejection, the problems of chronic rejection and xenograft rejection will be overcome, thus reversing the widening gap between organ demand and supply.