Autosomal Minor Histocompatibility Antigens: How Genetic Variants Create Diversity in Immune Targets

Abstract

Allogeneic stem cell transplantation (alloSCT) can be a curative treatment for hematological malignancies. Unfortunately, the desired anti-tumor or graft-versus-leukemia (GvL) effect is often accompanied with undesired side effects against healthy tissues known as graft-versus-host disease (GvHD). After HLA-matched alloSCT, GvL and GvHD are both mediated by donor-derived T-cells recognizing polymorphic peptides presented by HLA surface molecules on patient cells. These polymorphic peptides or minor histocompatibility antigens (MiHA) are produced by genetic differences between patient and donor. Since polymorphic peptides may be useful targets to manipulate the balance between GvL and GvHD, the dominant repertoire of MiHA needs to be discovered. In this review, the diversity of autosomal MiHA characterized thus far as well as the various molecular mechanisms by which genetic variants create immune targets and the role of cryptic transcripts and proteins as antigen sources are described. The tissue distribution of MiHA as important factor in GvL and GvHD is considered as well as possibilities how hematopoietic MiHA can be used for immunotherapy to augment GvL after alloSCT. Although more MiHA are still needed for comprehensive understanding of the biology of GvL and GvHD and manipulation by immunotherapy, this review shows insight into the composition and kinetics of in vivo immune responses with respect to specificity, diversity, and frequency of specific T-cells and surface expression of HLA-peptide complexes and other (accessory) molecules on the target cell. A complex interplay between these factors and their environment ultimately determines the spectrum of clinical manifestations caused by immune responses after alloSCT.

Keywords: T-lymphocytes; allogeneic stem cell transplantation; donor lymphocyte infusion; graft-versus-host disease; graft-versus-leukemia reactivity; hematological malignancy; immunotherapy; minor histocompatibility antigens.

Figure 1

Molecular mechanisms by which genetic variants create autosomal MiHA. Normal non-polymorphic sequences are indicated in gray, whereas alternative non-polymorphic sequences are shown in black. Polymorphic patient-specific sequences are shown in red and donor-specific sequences are indicated in green (if allelic variants exist). Whether the allelic variants are actually presented on the cell surface is also dependent on intracellular processing and presentation mechanisms, which are not taken into consideration in this figure. (A) MiHA created by SNPs in primary gene transcripts in the normal reading frame. (B) MiHA created by SNPs in primary gene transcripts in an alternative reading frame. (C) MiHA created by SNPs in 5´ or 3´ UTR of primary gene transcripts. (D) MiHA created by intron SNPs as retained in alternative gene transcripts. (E) MiHA derived from polymorphic proteins as created by frameshift insertions or deletions in primary gene transcripts. (F) MiHA derived from polymorphic proteins as created by SNP in alternative gene transcripts. (G) MiHA translated from intron sequences in polymorphic gene transcripts as created by exon or intron SNPs. (H) MiHA translated from polymorphic gene transcripts in which exon sequences are skipped as created by exon or intron SNPs. (I) MiHA encoded by polymorphic genes.