Improving organ allocation and protecting long-term graft function
The overall objective in this theme is to improve understanding of donor–recipient histocompatibility, to identify new ways to assess transplant immunological risk, and to introduce novel interventions to improve long-term graft function. We are using novel high-throughput techniques to type histocompatibility genes (human leucocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIR)) and investigate the role of natural killer cell activation in transplant rejection. We utilise computational molecular modelling techniques, structural information from X-ray crystallography and cryo-electron microscopy, and application of protein electrostatics theory to quantify the immunological risk associated with donor–recipient tissue incompatibility (donor HLA immunogenicity) and use this information to improve organ allocation policy (better tissue matching). We are also developing novel biophysical assays to characterise alloantibody–HLA interactions (microfluidic antibody affinity profiling) and assess the pathogenic potential of HLA-specific alloantibodies (a principal cause of long-term graft loss); this information can help improve access to transplantation (identify antibody compatible donor organs) and enable better assessment of recipient antibody responses after transplantation.
Theme Lead: Vasilis Kosmoliaptsis
Professor John Trowsdale
Collaborations within the BTRU
Theme 6: With Rachel Johnson (Theme 6 Lead and NHSBT Assistant Director Statistics and Clinical Studies) we are analysing national registry data to generate large-scale evidence for the introduction of a new UK-wide deceased-donor kidney allocation policy.
Theme 7: With Professor Menna Clatworthy’s group we are characterizing KIR gene profiles in renal transplant patients who have been subject to immunological rejection.
Collaborations with academic partners
We are working with Professor Tuomas Knowles, Department of Chemistry, University of Cambridge, to develop and apply a novel microfluidic platform to characterise alloantibody–HLA interactions in patient sera and to isolate and characterise extracellular vesicles as potential biomarkers in transplantation. We are also working with collaborators (Dr Andrew Leach and Dr Jose Marquez) at the European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) to investigate structural characteristics of HLA B-cell epitopes and of alloantibody–HLA complexes.
KIR-typing may allow identification of patients at high risk of transplant rejection. Better donor–recipient histocompatibility may improve long-term transplant outcomes and also improve access to transplantation by enabling allocation of organs to patients currently considered poor tissue matches and by reducing recipient sensitisation (alloantibody development) against potential donors. Similarly, better detection and characterisation of alloantibodies may improve assessment of immunological risk associated with a particular donor organ before transplantation and enable early intervention, before irreversible graft injury, after transplantation.
Other external funding
1. Jiang W, Johnson C, Simecek N, López-Álvarez MR, Di D, Trowsdale J, Traherne JA. qKAT: a high-throughput qPCR method for KIR gene copy number and haplotype determination. Genome Med. 2016 Sep 29; 8(1): 99 PubMed 27686127
2. Kosmoliaptsis V, Mallon DH, Chen Y, Bolton EM, Bradley JA, Taylor CJ. Alloantibody Responses after renal transplant failure can be better predicted by donor–recipient HLA amino acid sequence and physicochemical disparities than conventional HLA matching. Am J Transplant. 2016 Jul; 16(7): 2139–47 PubMed 26755448
3. Wiebe C, Kosmoliaptsis V, Pochinco D, Taylor C, Nickerson P. A comparison of HLA molecular mismatch methods to determine HLA immunogenicity. Transplantation 2018 Feb 13 PubMed 29443827
4. Mallon DH, Kling C, Robb M, Ellinghaus E, Bradley JA, Taylor CJ, Kabelitz D, Kosmoliaptsis V. Predicting humoral alloimmunity from differences in donor and recipient HLA surface electrostatic potential. J Immunol. 2018;201: 3780-92 PubMed 30429288
5. Copley HC, Elango M, Kosmoliaptsis V. Assessment of human leukocyte antigen immunogenicity: current methods, challenges and opportunities. Curr Opin Organ Transplant. 2018; 23: 477-85. PubMed 29870434
6. Wiebe C, Kosmoliaptsis V, Pochinco D, Gibson IW, Ho J, Birk PE, Goldberg A, Karpinski M, Shaw J, Rush DN, Nickerson PW. HLA-DR/DQ molecular mismatch: a prognostic biomarker for primary alloimmunity. Am J Transplant. 2019; 19: 1708-19. PubMed 30414349
7. Schneider MM, Scheidt T, Priddey AJ, Xu CK, Hu M, Devenish SRA, Meisl G, Dobson CM, Kosmoliaptsis V, Knowles TPJ. Microfluidic antibody affinity profiling for in-solution characterisation of alloantibody–hla interactions in human serum. bioRxiv