Aim: The significance of donor-specific HLA antibodies (DSA) in liver transplants is unclear, particularly in the context of ischemia-reperfusion injury (IRI) occurring during procurement and transplantation. The aim of this study was to identify mediators of injury, DSA and related poor outcomes in liver transplant recipients.
Methods: We evaluated donor-specific HLA antibodies (DSA), IRI status, and outcomes in 78 LT recipients using single antigen bead-based HLA antibody testing, intermediate-resolution HLA typing and histopathological biopsy assessment and reviewed available HLA expression data by RNA-Seq. Samples tested for DSA were defined as pre-, early (within 3 months), or late (after 6 months) post-transplant.
Results: Patients were grouped by patterns of longitudinal DSA (Fig 1A). IRI+ recipients typically displayed DSA early post-transplant (group 1), or early-to-late post-transplant (group 2), de novo at only the late timepoint (group 3) or persistent throughout all timepoints (group 6), whereas IRI- recipients were frequently DSA+ at pre-transplant and became negative either early (group 4) or late (group 5) post-transplant. Most patients without pre-transplant DSA who developed DSA post-transplant (groups 1-3) and those with persistent DSA across all timepoints (group 6) had DSA specificities of HLA-B and/or DQB1 as well as DPB1 for those with de novo (group 3) reactivity (Fig 1B). Groups 1-3 and 6 had the highest number of poor outcomes including EAD, ACR, AMR or death (Fig 1A). Pre-transplant DSA in recipients who became negative at early or late timepoints (groups 4-5) was specific to HLA-A, DR, or polyclonal across multiple HLA specificities (Fig 1B). Retrospective review of our previous RNAseq data on pre/post-reperfusion biopsies from 40 OLT recipients showed those with significant injury (IRI+; n=23) had increased post-reperfusion tissue expression of HLA-B, DQB1, and DPB1 (Fig 1C), suggesting increases in antigen availability due to IRI contribute to antigen-specific alloantibody production.
Conclusion: Baseline pre-transplant DSA assessment and IRI scoring can be used with post-transplant DSA monitoring in LT recipients to inform risk of poor post-transplant outcomes. Additionally, we have identified increased HLA-B/DQ/DP as potential therapeutic targets to reduce poor outcomes in LT recipients with significant injury.
