Abstract
Predicted Indirectly ReCognizable Human Leukocyte Antigen (HLA) Epitopes (PIRCHE) are known to be a significant risk factor for the development of donor HLA-specific antibodies after organ transplantation. Most previous studies on PIRCHE limited their analyses on the presentation of the HLA-DRB1 locus, although HLA-DRB3/4/5, -DQ, and -DP are also known for presenting allopeptides to CD4+ T cells. In this study, we analyzed the impact of predicted allopeptides presented by these additional loci on the incidence of HLA-specific antibodies after an immunization event. We considered pregnancy as a model system of an HLA immunization and observed child-specific HLA antibody (CSA) development of 231 mothers during pregnancy by samples being taken at delivery. Our data confirm that PIRCHE presented by HLA-DRB1 along with HLA-DRB3/4/5, -DQ, and -DP are significant predictors for the development of CSA. Although there was limited peptidome overlap observed within the mothers’ presenting HLA proteins, combining multiple presenting loci in a single predictor improved the model only marginally. Prediction performance of PIRCHE further improved when normalizing scores by the respective presenters’ binding promiscuity. Immunogenicity analysis of specific allopeptides could not identify significant drivers of an immune response in this small cohort, suggesting confirmatory studies.
Highlights
In solid organ transplantation, the recipient’s adaptive immune system is continuously faced with allogeneic human leukocyte antigen (HLA) proteins introduced by the donor organ
To the best of our knowledge, this is the first comprehensive investigation on the indirect pathway of allorecognition and its impact on Human Leukocyte Antigen (HLA) antibody formation based on highly resolved HLA typing data including the HLA-DRB3/4/5, -DQB1, -DQA1, -DPB1, and -DPA1 loci
We conducted our study on three levels: determination/ comparison of i) the numeric degree of allopeptide presentation (i.e., PIRCHE score (PS)) on each of the investigated HLA Class II loci, their origin, and their respective overlap with each of the investigated HLA Class II loci; ii) the impact of elevated PS on child-specific HLA antibody (CSA)+ incidence; and iii) the immunogenicity of the identified presented allopeptides and their expected contribution to CSA induction
Summary
The recipient’s adaptive immune system is continuously faced with allogeneic human leukocyte antigen (HLA) proteins introduced by the donor organ. The Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE-II) algorithm is designed to estimate allorecognition via the indirect pathway. It estimates the number of donor HLA protein-derived peptides that are predicted to be presented within the binding cleft of the recipient’s HLA Class II molecules on antigen-presenting cells [2]. The number of HLA epitopes presentable within donor DR heterodimers were previously shown to correlate with the development of posttransplant de novo DSA and graft survival in kidney, liver, and heart transplantation [4,5,6,7], and with the development of child-specific HLA antibodies (CSA) in pregnancy [8]
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