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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

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
Katso/Avaa
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FRONTIERS MEDIA SA
doi:10.3389/fimmu.2019.01625
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042713207
Tiivistelmä
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.
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