Abstract
Patients undergoing allogeneic stem cell transplantation as treatment for hematological diseases face the risk of Graft-versus-Host Disease as well as relapse. Graft-versus-Host Disease and the favorable Graft-versus-Leukemia effect are mediated by donor T cells recognizing polymorphic peptides, which are presented on the cell surface by HLA molecules and result from single nucleotide polymorphism alleles that are disparate between patient and donor. Identification of polymorphic HLA-binding peptides, designated minor histocompatibility antigens, has been a laborious procedure, and the number and scope for broad clinical use of these antigens therefore remain limited. Here, we present an optimized whole genome association approach for discovery of HLA class I minor histocompatibility antigens. T cell clones isolated from patients who responded to donor lymphocyte infusions after HLA-matched allogeneic stem cell transplantation were tested against a panel of 191 EBV-transformed B cells, which have been sequenced by the 1000 Genomes Project and selected for expression of seven common HLA class I alleles (HLA-A∗01:01, A∗02:01, A∗03:01, B∗07:02, B∗08:01, C∗07:01, and C∗07:02). By including all polymorphisms with minor allele frequencies above 0.01, we demonstrated that the new approach allows direct discovery of minor histocompatibility antigens as exemplified by seven new antigens in eight different HLA class I alleles including one antigen in HLA-A∗24:02 and HLA-A∗23:01, for which the method has not been originally designed. Our new whole genome association strategy is expected to rapidly augment the repertoire of HLA class I-restricted minor histocompatibility antigens that will become available for donor selection and clinical use to predict, follow or manipulate Graft-versus-Leukemia effect and Graft-versus-Host Disease after allogeneic stem cell transplantation.
Highlights
Allogeneic stem cell transplantation has a curative potential for treatment of hematological malignancies [1, 2]
The six patients underwent allogeneic stem cell transplantation for the treatment of acute myeloid leukemia (AML), chronic myeloid leukemia (CML) or myelodysplastic syndrome (MDS) and developed a clinical immune response after donor lymphocyte infusions (DLI) characterized by Graft-versus-Host Disease (GvHD) or disappearance of patient cells in bone marrow or peripheral blood
In order to develop a more efficient whole genome association scanning (WGAs) method to identify minor histocompatibility antigens, 191 EBV-LCLs of the 1000 Genomes Project were selected for expression of seven common HLA class I alleles
Summary
Allogeneic stem cell transplantation (alloSCT) has a curative potential for treatment of hematological malignancies [1, 2]. Donor T cells that are present in the stem cell graft or DLI induce beneficial Graft-versus-Leukemia (GvL) reactivity as well as undesired GvHD by targeting polymorphic peptides, designated minor histocompatibility antigens [4,5,6]. Minor histocompatibility antigens are peptides produced by single nucleotide polymorphisms (SNPs), which differ between patient and donor, and are presented by HLA molecules on the cell surface [4,5,6]. They are similar to neoantigens with respect to amino acid changes that are recognized by the immune system, but are encoded by germline polymorphisms instead of somatic mutations [7]. Donor T cells recognizing antigens that are broadly expressed on malignant cells and healthy tissues may induce GvL reactivity as well as GvHD, while donor T cells targeting antigens that are only expressed on (malignant) hematopoietic cells selectively mediate a GvL effect without GvHD
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