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.
Highlights
Acute and chronic GVHD and recurrent or progressive malignancy (i.e., “relapse”) represent major outcomes that determine the success of allogeneic hematopoietic cell transplantation (HCT)
The cumulative incidence frequencies of grades 2-4 and grades 3-4 acute GVHD were higher in the Fred Hutchinson Cancer Research Center (FHCRC) cohort (0.64 and 0.17, respectively) than in the CIBMTR cohort
The cumulative incidence frequencies of chronic GVHD and relapse were similar in the 2 cohorts (Figure 1)
Summary
Acute and chronic GVHD and recurrent or progressive malignancy (i.e., “relapse”) represent major outcomes that determine the success of allogeneic hematopoietic cell transplantation (HCT). Acute and chronic GVHD reflect immune-mediated injury mediated by donor cells in recipient tissues, and to some extent, relapse represents a lack of immune-mediated attack on malignant cells that remain viable in the recipient after the pretransplant conditioning regimen. Donor T cells can recognize both major and minor histocompatibility antigens (mHAgs) in HLA-mismatched recipients, but in HLA-matched sibling recipients, donor T cells recognize only mHAgs [1, 2]. DNA sequence and structural variation between siblings generates mHAg mismatching between recipients and. Amino acid differences resulting from single nucleotide polymorphisms (SNP), insertions and deletions (indels) and other types of variants represent well-recognized mechanisms that generate mHAgs [1,2,3,4]
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