Indirect recognition of HLA epitopes in solid organ transplantation

Abstract

Alloreactivity due to HLA mismatches between donor and recipient remains the major limiting factor in successful graft outcome after solid organ transplantation. However, the immunogenicity of individual HLA mismatches is highly variable. Therefore, epitope-based HLA matching may be a sophisticated method for solid organ transplantation. In epitope-based HLA matching, donor and recipient are matched based on clinically relevant epitopes that are located on HLA. In this thesis we describe PIRCHE-II (Predicted Indirectly ReCognizable HLA epitopes) as a method for epitope-based HLA matching in solid organ transplantation. The PIRCHE-II algorithm predicts indirect T cell recognition by predicting mismatched HLA-derived epitopes that can be presented on HLA class II molecules of the recipient. The aim of this thesis was to elucidate and to improve the applicability of PIRCHE-II in solid organ transplantation and to investigate the role of PIRCHE-II in HLA antibody formation and graft failure in different HLA sensitizing events. In the first part of the thesis we further improved the PIRCHE infrastructure to facilitate the clinical application of the PIRCHE-II algorithm. In the PIRCHE algorithm, PIRCHE numbers are calculated based on amino acid polymorphisms between donor and recipient. To be able to identify these amino acid polymorphisms between donor and recipient, the complete amino acid sequence has to be available. The complete amino acid sequence is required at two levels: [1] the complete amino acid sequence of all identified HLA alleles need be available for setting-up the PIRCHE database, and [2] high- or allelic-resolution HLA typing of both donor and recipient need to be available as input for the PIRCHE algorithm, as serological typing does not provide detailed information on the exact allelic variation between HLA alleles. To solve the first problem, we used an automated nearest-neighbor-based approach to extrapolate incomplete HLA sequences that were present in the IMGT/HLA database to obtain the complete amino acid sequence of these incomplete HLA sequences. To solve the second problem, we developed a computational approach to calculate PIRCHE-II values using serological split level HLA typing as input for the algorithm. In the second part of the thesis we describe how we might apply the PIRCHE-II algorithm in different HLA sensitization settings. We showed that the number of PIRCHE-II presented by HLA-DRB1 was related to the formation of HLA antibodies during pregnancy as well as after pancreas and pancreatic islet transplantation. However, in women with a successful pregnancy that was preceded by a previous miscarriage we observe a different HLA sensitization pattern and the number of PIRCHE-II was not related to HLA antibody formation. We also investigated the role of PIRCHE-II in graft failure after kidney transplantation. We showed that the number of PIRCHE-II was related with graft failure after kidney transplantation, indicating that PIRCHE-II may be a useful tool to identify permissible HLA mismatches in solid organ transplantation. In conclusion, the findings in this thesis suggest that the PIRCHE-II algorithm may provide the opportunity to identify permissible HLA mismatches in solid organ transplantation, thereby minimizing HLA sensitization and prolonging graft survival.