OR7 MiHAIP: Comprehensive pipeline to discover immunogenic minor histocompatibility antigens via whole genome sequences of HLA-matched donor-recipient pairs

Abstract

Aim Allogeneic hematopoietic cell transplantation (AlloHCT) is a curative therapy for certain hematological malignancies, immune deficiencies and inborn errors of metabolism. A major complication of alloHCT is graft-versus-host disease (GVHD) mediated by immunogenic minor histocompatibility antigens (MiHAs). To date, a limited number of MiHAs with HLA restrictions have been identified and well characterized. We developed a comprehensive pipeline to predict potential MHC class I-restricted MiHAs. Methods The MiHA identification pipeline (MiHAIP) integrates diverse biological data sources, including whole genome sequences, HLA genotypes, clinical outcomes, tissue-specific expression, known MiHAs, and minor allele frequencies. MiHAIP incorporates third-party bioinformatics toolboxes, such as RTGtools, snpEff, netchop-3.1 and netMHCpan-3.0, to predict the potential MiHAs in parallel by comparing variants between the donor and recipient. Subsequently, the pipeline simulates antigen processing and presentation on recipients’ cell surface via HLA molecule restriction (figure). Results Whole genome sequences and HLA typing of a cohort of unrelated donor-recipient pairs (n = 205) were loaded to MiHAIP to predict potential MiHAs. It takes on average 22 min to process each donor-recipient pair of whole genome sequence data on a cloud computing environment. Known autosomal MiHAs were examined to validate the sensitivity of the pipeline. MiHAIP outputs the predicted HLA-restricted antigens and their potential GVHD effects. Conclusions The proposed MiHAIP is the first MHC class I-restricted MiHA prediction tool for analyzing whole genome sequences of donor-recipient pairs with HLA matches. It accurately and efficiently identifies known well-characterized MiHAs and new potential MiHAs with high sensitivity.