PUBLISHED BY
Niemann, Matthias; Strehler, Yara; Lachmann, Nils; Halleck, Fabian; Budde, Klemens; Hönger, Gideon; Schaub, Stefan; Matern, Benedict M.; Spierings, Eric
PUBLISHED IN
Frontiers in Immunology
PATIENTS
536
ABSTRACT
Development of donor-specific human leukocyte antigen (HLA) antibodies (DSA) remains a major risk factor for graft loss following organ transplantation, where DSA are directed towards patches on the three-dimensional structure of the respective organ donor’s HLA proteins. Matching donors and recipients based on HLA epitopes appears beneficial for the avoidance of DSA. Defining surface epitopes however remains challenging and the concepts underlying their characterization are not fully understood. Based on our recently implemented computational deep learning pipeline to define HLA Class I protein-specific surface residues, we hypothesized a correlation between the number of HLA protein-specific solvent-accessible interlocus amino acid mismatches (arbitrarily called Snowflake) and the incidence of DSA. To validate our hypothesis, we considered two cohorts simultaneously. The kidney transplant cohort (KTC) considers 305 kidney-transplanted patients without DSA prior to transplantation. During the follow-up, HLA antibody screening was performed regularly to identify DSA. The pregnancy cohort (PC) considers 231 women without major sensitization events prior to pregnancy who gave live birth. Post-delivery serum was screened for HLA antibodies directed against the child’s inherited paternal haplotype (CSA). Based on the involved individuals’ HLA typings, the numbers of interlocus-mismatched antibody-verified eplets (AbvEPS), the T cell epitope PIRCHE-II model and Snowflake were calculated locus-specific (HLA-A, -B and -C), normalized and pooled. In both cohorts, Snowflake numbers were significantly elevated in recipients/mothers that developed DSA/CSA. Univariable regression revealed significant positive correlation between DSA/CSA and AbvEPS, PIRCHE-II and Snowflake. Snowflake numbers showed stronger correlation with numbers of AbvEPS compared to Snowflake numbers with PIRCHE-II. Our data shows correlation between Snowflake scores and the incidence of DSA after allo-immunization. Given both AbvEPS and Snowflake are B cell epitope models, their stronger correlation compared to PIRCHE-II and Snowflake appears plausible. Our data confirms that exploring solvent accessibility is a valuable approach for refining B cell epitope definitions.
HIGHLIGHTS
- First clinical validation of Snowflake algorithm in two clinical cohorts.
- 305 kidney transplant monitored for donor-specific HLA antibodies (DSA).
- 231 pregnant women monitored for child-specific HLA antibodies (CSA)- Comparison of Eplet matching (AbV and non-AbV), PIRCHE and Snowflake.
- In DSA/CSA-positive cases, Snowflake scores were elevated- Snowflake scores correlate stronger with Eplet scores than with PIRCHE.