Abstract
For hundreds of thousands of years, the human genome has extensively evolved, resulting in genetic variations in almost every gene. Immunological reflections of these genetic variations become clearly visible after an allogeneic stem cell transplantation (allo-SCT) as minor Histocompatibility (H) antigens. Minor H antigens are peptides cleaved from genetically encoded variable protein regions after which they are presented at the cell surface by HLA molecules. After allo-SCT with minor H antigen mismatches between donor and recipient, donor T cells recognize the minor H antigens of the recipient as foreign, evoking strong alloreactive immune responses. Studies in the late eighties have discovered that a subset of minor H antigens are encoded by hematopoietic system-specific genes. After allo-SCT, this subset is strictly expressed on the hematopoietic malignant cells and was therefore the first well-defined highly immunogenic group of tumor-specific antigens. In the last decade, neoantigens derived from genetic mutations in tumors have been identified as another group of immunogenic tumor-specific antigens. Therefore, hematopoietic minor H antigens and neoantigens are therapeutic equivalents. This review will connect our current knowledge about the immune biology and identification of minor H antigens and neoantigens leading to novel conclusions on their prediction.
Highlights
Minor H Antigens: From Enigmatic to Well-Defined Transplantation-AntigensToday, more than six decades after the first application of allogeneic stem cell transplantation, scientists and clinicians are still impressed by the therapeutic Graft-versus-Tumor (GvT) effect established by donor T cells administered along with stem cells into the recipient [1]
The main mediators of GvHD as well as GvT are the alloreactive donor T cells directed at recipient antigens that are absent in the donor, responding to Major Histocompatibility Complex
single nucleotide polymorphisms (SNPs)-induced differential processing was found for an HLA class II (HLA-II) restricted minor H antigen [95], indicating that development of HLA-II epitope processing prediction algorithms may be valuable for future identification of immunogenic HLA-II presented antigens
Summary
Minor H Antigens: From Enigmatic to Well-Defined Transplantation-AntigensToday, more than six decades after the first application of allogeneic stem cell transplantation (allo-SCT), scientists and clinicians are still impressed by the therapeutic Graft-versus-Tumor (GvT) effect established by donor T cells administered along with stem cells into the recipient [1]. There is still much room for improvement of the reverse approach, which in theory is the best directed and straight forward strategy to identify HLA-I restricted hematopoiesis-specific minor H antigens as well as neoantigens. Some pioneering studies have combined minimalistic in silico analyses, without including antigen processing or HLA-binding predictions, but with large plasmid- or peptide-library screening strategies to identify HLAII restricted neoantigen-specific T cell responses in cancer patients [67, 74, 75].
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