NEW WHOLE GENOME ASSOCIATION SCANNING APPROACH FOR THE DISCOVERY OF HLA CLASS I-RESTRICTED MINOR HISTOCOMPATIBILITY ANTIGENS
Author(s): ,
Kyra Fuchs
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands
,
Alwin Adriaans
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands
,
Willy Honders
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands
,
Dyantha van der Lee
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands
,
Edith van der Meijden
Affiliations:
Department of Internal Medicine, Hematology and Internal Oncology,University Hospital Erlangen,Erlangen,Germany
,
Margot Pont
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands;Division of Clinical Research,Fred Hutchinson Cancer Research Center,Seattle,United States
,
Ramin Monajemi
Affiliations:
Department of Medical Statistics,LUMC,Leiden,Netherlands
,
Szymon Kielbasa
Affiliations:
Department of Medical Statistics,LUMC,Leiden,Netherlands
,
Peter 't Hoen
Affiliations:
Department of Human Genetics,LUMC,Leiden,Netherlands;Centre for Molecular and Biomolecular Informatics,Radboud University Medical Center Nijmegen,Nijmegen,Netherlands
,
Cornelis van Bergen
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands
,
Frederik Falkenburg
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands
Marieke Griffioen
Affiliations:
Department of Hematology,LUMC,Leiden,Netherlands
EHA Library. Fuchs K. Jun 15, 2019; 267473; S890
Kyra Fuchs
Kyra Fuchs
Contributions
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Abstract

Abstract: S890

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 16:00 - 16:15

Location: Hall 3A

Background
Patients that undergo allogeneic stem cell transplantation (SCT) as treatment for hematological diseases face the risk of relapse as well as Graft-versus-Host Disease (GvHD). GvHD as well as the favorable Graft-versus-Leukemia effect are mediated by donor T cells. These T cells recognize minor histocompatibility antigens: polymorphic peptides, which are presented on the cell surface by HLA molecules and are caused by genetic differences in single nucleotide polymorphisms (SNPs) between patient and donor. Knowledge about mismatched minor histocompatibility antigens may enable a more directed donor search as well as better prediction and measurement of the Graft-versus-Leukemia effect and GvHD for personalized treatment after transplantation, thereby contributing to a better outcome for patients treated with allogeneic SCT.

Aims
Identification of minor histocompatibility antigens has been a laborious process in the past. Therefore, whole genome association scanning was developed in our laboratory. However, this method was restricted to two HLAs and screening of one million SNPs. The aim of this study is to develop and use an optimized method to identify the dominant repertoire of minor histocompatibility antigens in common HLA class I alleles. 

Methods
Donor T-cells isolated from patients after allogeneic SCT are tested for recognition of a new panel of 191 selected B-cell lines, which are sequenced in the 1000 Genome Project. This panel enables the inclusion of seven common HLAs and increases SNP coverage to 12 million (MAF > 0.01). SNPs that strongly associate with T-cell recognition are subsequently validated to encode minor histocompatibility antigens.

Results
A total of 19 novel minor histocompatibility antigens have been identified that are presented in seven common HLA class I alleles, showing the potential of this optimized approach. Besides conventional antigens, cryptic peptides were found as well as peptides restricted to HLAs that were not primarily targeted.

Conclusion
This improved approach for whole genome association scanning has been successfully applied in rapidly discovering new minor histocompatibility antigens. The new method surpasses previous methods in its rapidness and coverage of HLAs and SNPs across the human genome, which additionally allows for identification of cryptic peptides. With the increasing number of patients that are analyzed in this study, T-cells recognizing known minor histocompatibility antigens are more often isolated, indicating that the repertoire of minor histocompatibility antigens is limited. Our optimized method is expected to discover the majority of unknown antigens in this repertoire, thereby contributing essential knowledge for new strategies to improve clinical outcome after allogeneic SCT. 

Session topic: 21. Stem cell transplantation - Experimental

Keyword(s): Allogeneic hematopoietic stem cell transplant, Graft-versus-host disease (GVHD), Graft-versus-leukemia, Minor histocompatibility antigen

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