Title: Computational assessment of Human Leukocyte Antigen immunogenicity to improve donor-recipient histocompatibility and inform allocation policy in kidney transplantation and beyond
Funder: Department of Health and Social Care

Abstract: Donor and recipient HLA matching is a central objective of solid organ and haematopoietic stem cell transplant (HSCT) allocation policies. In kidney transplantation HLA matching helps offset the risk of antibody mediated rejection and long-term graft failure but existing matching algorithms for kidney allocation are inadequate as they assign equal weighting to all donor HLA mismatches, despite wide variation of donor HLA immunogenicity according to recipient HLA type. Our research has been at the forefront of efforts to describe more intelligent ways to assess donor and recipient histocompatibility. We have developed and validated a novel computational tool that enables prediction of donor HLA immunogenicity based on assessment of structural and physicochemical differences between donor and recipient HLA molecules (Cambridge HLA immunogenicity algorithm). The proposed project aims to refine this work and provide comprehensive evidence to inform a new deceased-donor kidney allocation policy. Important evidence will also be provided to demonstrate the potential of this approach to improve access to transplantation and clinical outcomes after HSCT. Work package-1: In collaboration with NHS Blood and Transplant (NHSBT), we will investigate alloantibody responses after kidney transplant failure in a large national patient cohort. Over 10,000 donor-recipient HLA mismatched combinations will be examined making this the largest HLA immunogenicity study to date. Logistic regression models will be used to assess whether evaluation of HLA immunogenicity based on our algorithm enables prediction of donor-specific HLA class I and class II antibody development. We will also examine whether our approach enables better assessment of the risk of overall recipient sensitisation against the potential organ donor pool compared to conventional HLA mismatch grade. Work package-2: In collaboration with NHSBT, we will examine transplant outcomes in a national consecutive cohort of patients that underwent deceased-donor kidney transplantation in the UK (n=17,527). Multifactorial proportional hazards regression models will be used to establish conclusively whether assessment of donor-recipient HLA compatibility based on the Cambridge HLA immunogenicity algorithm is superior to conventional HLA matching as a strategy to improve long-term graft survival after kidney transplantation. Work package-3: We anticipate that the above work will provide comprehensive evidence for the clinical utility of our HLA matching algorithm and the factors influencing post-transplant outcome. This information along with equity of access factors will be considered in extensive computer simulations using actual UK registry data to provide evidence for an improved deceased-donor kidney allocation scheme that incorporates the Cambridge HLA immunogenicity algorithm. Work package-4: HSCT is a potentially curative treatment option for life-threatening haematological disorders but often necessitates the selection of HLA mismatched unrelated donors; in this setting, acute graft-versus-host disease (GVHD) represents a major barrier to successful outcomes. We have generated preliminary evidence that our algorithm can identify HLA mismatched HSCT grafts with similar incidence of acute GVHD to fully HLA matched grafts. Building on this background, we aim to perform a large, multicentre UK study using registry data to provide strong evidence for the potential of the Cambridge HLA immunogenicity algorithm to improve donor selection and clinical outcomes after HSCT. The proposed research can benefit the many patients undergoing renal transplantation in the UK and more widely through better kidney allocation and improved long-term outcomes; and through improved access to transplantation (by enabling kidney allocation to patients that are currently considered a poor tissue match and by reducing alloantibody development facilitating access to future re-transplantation). Moreover, by enhancing options for donor selection and improving clinical outcomes, the proposed research has the potential to introduce a step change in the management of patients that need allogeneic HSCT.

Lay abstract: Renal transplantation is the optimal treatment for patients with end-stage renal failure. It prolongs and enhances quality of life and is more cost-effective compared to renal replacement therapy (dialysis). Approximately 3,200 kidney transplants are performed each year in the UK but despite efforts to increase the availability of donor organs, the size of the kidney transplant waiting list has remained largely unchanged reflecting the constant demand for more organs. A major challenge, therefore, in organ transplantation is to ensure that graft survival is maximised. Although early results after transplantation are excellent, long-term outcomes have remained static and over 30% of kidney transplants fail within 10 years. This is due to a process called chronic rejection' which occurs mainly due to development of antibodies against special proteins expressed by the donor organ (called Human Leukocyte Antigens or HLA). These histocompatibility proteins vary widely in individuals, both within and between different ethnic groups. The risk of antibody-mediated rejection can be offset by ensuring donor kidneys are allocated to recipients with a good tissue-match (donor and recipient share as many HLA proteins as possible) but current methods for determining tissue compatibility are inadequate. This is because they simply enumerate HLA differences between a donor and a potential recipient without considering the molecular and structural differences between their HLA proteins. Another implication of tissue incompatibility and donor-specific antibody development is that they compromise future access to re-transplantation should the first kidney transplant fail. The latter is a significant clinical problem considering that over one fifth of approximately 5,700 patients currently listed for renal transplantation in the UK are awaiting a repeat transplant and most have developed donor-specific antibodies (called alloantibodies). Beyond kidney transplantation, HLA compatibility is crucial for the success of haematopoietic stem cell transplants (HSCT; otherwise known as bone marrow transplants). HLA-identical sibling donors lead to the best clinical outcomes but are commonly not available necessitating the selection of unrelated, less well matched donors that are associated with poorer outcomes. The main focus of our research is on investigating better ways to assess donor and recipient tissue compatibility. We have studied the structure and physical properties of HLA proteins using advanced computational molecular modelling tools and showed that the degree of donor and recipient histocompatibility can be assessed based on structural and physicochemical differences between their HLA proteins. To this extent, we have developed and validated a novel computerised algorithm that enables quantification of structural and physicochemical differences between donor and recipient HLA proteins to derive a matchability' score. As a practical example, if a kidney donor has the same number of HLA differences with two potential recipients, our algorithm helps identify the donor-recipient combination that is more likely to lead to a successful post-transplant outcome in terms of alloantibody development and graft survival. In collaboration with NHS Blood and Transplant, we now propose to perform two large, national clinical studies that we anticipate will provide strong evidence that assessment of donor and recipient histocompatibility based on our algorithm is superior to conventional HLA matching as a strategy to reduce the detrimental effect of post-transplant alloantibody responses and improve long-term graft survival after kidney transplantation. Extensive computer simulation studies will also be performed, using actual UK registry data, to inform a new national deceased-donor kidney allocation scheme that incorporates our algorithm. Finally, a large national study will be undertaken to provide further evidence for the potential of our algorithm to improve donor selection and clinical outcomes after HSCT. Development of the proposed research has already benefited from direct input from patients. We have plans in place to enable further patient and public involvement that will enhance the conduct of the study by contributing to data interpretation and to formulation of future research questions; and by assisting with broadening the accessibility and dissemination of findings. We will also work in close partnership with NHS Blood and Transplant and their patient representative groups to ensure strong public and patient engagement to help translate research findings into UK transplant policy. Overall, the proposed research can benefit the many patients undergoing renal transplantation in the UK and more widely through better kidney allocation and improved long-term outcomes; and through improved access to transplantation (by enabling kidney allocation to patients that are currently considered a poor tissue match and by reducing alloantibody development facilitating access to future re-transplantation). Moreover, by enhancing options for donor selection and improving clinical outcomes, the proposed research has the potential to introduce a step change in the management of patients that need HSCT.

Research activity codes: 6.4 SURGERY
Health categories: RENAL AND UROGENITAL