Abstract
Genetic mismatches in protein coding genes between allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipient and donor can elicit an alloimmunity response via peptides presented by the recipient HLA receptors as minor histocompatibility antigens (mHAs). While the impact of individual mHAs on allo-HSCT outcome such as graft-vs.-host and graft-vs.-leukemia effects has been demonstrated, it is likely that established mHAs constitute only a small fraction of all immunogenic non-synonymous variants. In the present study, we have analyzed the genetic mismatching in 157 exome-sequenced sibling allo-HSCT pairs to evaluate the significance of polymorphic HLA class I associated peptides on clinical outcome. We applied computational mismatch estimation approaches based on experimentally verified HLA ligands available in public repositories, published mHAs, and predicted HLA-peptide affinites, and analyzed their associations with chronic graft-vs.-host disease (cGvHD) grades. We found that higher estimated recipient mismatching consistently increased the risk of severe cGvHD, suggesting that HLA-presented mismatching influences the likelihood of long-term complications in the patient. Furthermore, computational approaches focusing on estimation of HLA-presentation instead of all non-synonymous mismatches indiscriminately may be beneficial for analysis sensitivity and could help identify novel mHAs.
Highlights
Allogeneic hematopoietic stem cell transplantation presents a potentially curative treatment for a variety of malignant diseases and other serious disorders of the blood and hematopoietic system
We have carried out a computational analysis of class I human leukocyte antigen (HLA) peptide binding affinity and immunogenicity potential, included epithelial protein expression data and enumerated the presence of experimentally verified HLA ligands and minor histocompatibility antigens (mHAs) available in the public domain to evaluate the capability of these different approaches to estimating long-term alloreactivity capacity
The HLA-A and -B receptor binding affinity predictions to the unique peptides of the HSCT recipients were performed with the Immune Epitope Database (IEDB) tool predict_binding.py v2.17 using the IEDB_recommended option which combines the results of multiple prediction algorithms [32,33,34,35,36,37]
Summary
Allogeneic hematopoietic stem cell transplantation (alloHSCT) presents a potentially curative treatment for a variety of malignant diseases and other serious disorders of the blood and hematopoietic system. In contrast to mHAs, the relatively large amount of available experimental HLA ligands allows both statistical estimates with higher confidence and analyses in conjunction with other external data sets Comparison of this approach with established methods is needed to better understand alloreactivity and its computational modeling. To this end, we have carried out a computational analysis of class I HLA peptide binding affinity and immunogenicity potential, included epithelial protein expression data and enumerated the presence of experimentally verified HLA ligands and mHAs available in the public domain to evaluate the capability of these different approaches to estimating long-term alloreactivity capacity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
