Postdoctoral Research Fellow Duke University Durham, NC
Aim: Xenotransplantation, the use of genetically modified pigs as organ donors for human transplantation, recently received clinical trial FDA approval. The inclusion criteria for enrollment are patients who are more likely to die or go untransplanted than receive a kidney transplant in the next five years. Highly sensitized patients - those with antibodies against human major histocompatibility complex (HLA-MHC) – fit these criteria and are likely to be considered as participants in the first clinical trial. While there is evidence that some anti-HLA-MHC antibodies can cross-react with the donor pig MHC in an epitope-restricted manner, no current era study has characterized the prevalence of homologous and potentially crossreactive human MHC epitopes in the pig SLA-MHC (swine leukocyte antigen, SLA).
Methods: Our MHC Matchmaker algorithm is based on a curated database of all available pig and human amino acid MHC sequences in the IMGT database (accessed September 1st, 2024). These sequences are aligned against a common consensus and the relative solvent accessibility score is calculated from NetSurfP-3.0 Python script developed to compare and collate amino acid differences. MHC Matchmaker algorithm performance for HLA comparisons was compared to HLA Matchmaker, using a linear regression of a random sampling of 1000 HLA alleles.
Results: We successfully generated an algorithm to evaluate amino acid differences, which may serve as immunogenic epitopes, across species and rank donor-recipient pairs based on these differences. Results from our algorithm compared favorably to HLA Matchmaker, with a Pearson correlation coefficient of r2 of 0.72 and 0.74 for class I and class II MHC respectively (Figure 1). Equally important, we identified several HLA amino acid motifs registered in the HLA Eplet Registry that were not found in across SLA alleles (Table 1).
Conclusion: An algorithm was successfully generated that could compare and rank MHC similarities and disparities across species – specifically pig-to-human as it relates to xenotransplantation. Additionally, we identified several HLA eplets that were not found in the SLA. For highly sensitized patients, this tool may aid in risk assessments and predictions for negative crossmatch tests. Validation of HLA antibody interactions with shared SLA amino acid motifs is in progress.
