Predictive Biomarkers of Response to Desensitisation in Renal Transplantation

Abstract

Human leukocyte antigen incompatible (HLAi) transplantation is an important option for very highly sensitised patients with poor chances of receiving a compatible donor offer. However, crossing the HLA barrier is associated with an increased risk of antibody-mediated rejection (AMR) and graft failure. Desensitisation, induction and maintenance immunosuppression aim to minimise this risk. However, there is poor consensus on the optimal desensitisation protocol and patient response to treatment is known to vary. We assessed incidence of rejection and graft survival in a clinical cohort of 27 HLAi transplant recipients desensitised with rituximab followed by cycles of double filtration plasmapheresis (DFPP). Overall, there was poor association between known risk factors and incidence of AMR, suggesting the involvement of other, currently unknown, factors. HLA antibody response and AMR are known influenced by a complex cytokine network supporting the generation and survival of antibody producing cells. We conducted a literature review to grade of 459 protein analytes based on the level and quality of evidence of each analyte’s involvement in humoral memory response. We evaluated the serum concentrations of 40 serum protein analytes (cytokines, chemokines, hormones and growth factors with involvement in B-cell/plasma cell support) using a bespoke multiplexed Luminex assay, in order to characterise the longitudinal effects of the immunosuppressive protocols and potentially identify profiles associated with clinical outcome. We assessed serum samples, derived from the 27 HLAi transplant recipients, pre- and post-desensitisation and post-transplant. The results revealed great diversity of patient immune profiles and significant and sustained alteration of the supportive and regulatory signals that influence antibody producing cells and their precursors. However, we were not able to identify an association between the concentration profiles of the biomarkers and patient clinical outcomes, including early and late rejection.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Madhvi Menon (Supervisor) & Tracy Hussell (Supervisor)