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



: Ritari J, Hyvärinen K, Koskela S, Niittyvuopio R, Nihtinen A, Salmenniemi U, Putkonen M, Volin L, Kwan T, Pastinen T, Itälä-Remes M, Partanen J

Publisher: FRONTIERS MEDIA SA

: 2019

: Frontiers in Immunology

: FRONTIERS IN IMMUNOLOGY

: FRONT IMMUNOL

: ARTN 1625

: 10

: 9

: 1664-3224

DOI: https://doi.org/10.3389/fimmu.2019.01625

: https://research.utu.fi/converis/portal/detail/Publication/41686395


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.

Last updated on 2024-26-11 at 18:24