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Front Immunol. 2019 Jul 16;10:1625. doi: 10.3389/fimmu.2019.01625. eCollection 2019.

Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease After Allogeneic HSCT.

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Finnish Red Cross Blood Service, Helsinki, Finland.
Stem Cell Transplantation Unit, Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
Stem Cell Transplantation Unit, Division of Medicine, Department of Hematology, Turku University Hospital, Turku, Finland.
Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, QC, Canada.
Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO, United States.


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.


HLA; HSCT; genomics; graft-vs.-host; minor histocompatibility antigen; whole-exome sequencing

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