A Model of Minor Histocompatibility Antigens in Allogeneic Hematopoietic Cell Transplantation

Abstract

Minor histocompatibility antigens (mHAg) composed of peptides presented by HLA molecules can cause immune responses involved in graft-versus-host disease (GVHD) and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (HCT). The current study was designed to identify individual graft-versus-host genomic mismatches associated with altered risks of acute or chronic GVHD or relapse after HCT between HLA-genotypically identical siblings. Our results demonstrate that in allogeneic HCT between a pair of HLA-identical siblings, a mHAg manifests as a set of peptides originating from annotated proteins and non-annotated open reading frames, which i) are encoded by a group of highly associated recipient genomic mismatches, ii) bind to HLA allotypes in the recipient, and iii) evoke a donor immune response. Attribution of the immune response and consequent clinical outcomes to individual peptide components within this set will likely differ from patient to patient according to their HLA types.

Associations of Minor Histocompatibility Antigens with Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation

“…Similar findings have been previously reported – a study identified recipient allele mismatch associations (i.e., allele mismatches that have the potential to encode mHAs) that were associated with increased relapse in patients with HLA-A*02:01. 6 It may be possible that these immunodominant mHAs compete with and limit HLA presentation of other immunogenic antigens and therefore suppress immune responses towards tumor cells, though there is no evidence to support this in this context. A similar mechanism has been described in the setting of cancer vaccination, where Listeria monocytogenes antigens have been theorized to suppress immunogenicity of target vaccine antigens.…”

“…Prior studies have identified SNPs associated with outcomes, but these studies identified genomic variants rather than mHA peptides. 6,7…”

“…Prior studies have identified SNPs associated with outcomes, but these studies identified genomic variants rather than mHA peptides. 6,7 (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…Prior studies have identified SNPs associated with outcomes, but these studies identified genomic variants rather than mHA peptides. 6,7 More recently, "reverse immunology" approaches have utilized genomic sequencing & other bioinformatic tools to predict the entire mHA landscape of donor-recipient pairs (DRPs) following alloHCT. [8][9][10][11] This approach has allowed studies to assess the impact of the predicted mHA repertoire on outcomes.…”

Milestones in acute GVHD pathophysiology

“…In the late ‘70s, another piece of complexity was introduced with the advent of minor histocompatibility antigens (mi-Ha) in mice that led to GVHD but was prevented by the removal of T-lymphocytes from the graft ( 23 ). It then took 20 years before the role of mi-Ha was strongly suggested in humans ( 24 ), although the role of individual mi-Ha remains controversial ( 25 ).…”