Abstract
Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation.
Highlights
Graft-vs.-host Disease (GVHD) represents a significant cause of morbidity and mortality in stemcell transplant (SCT) recipients [1]
The Virginia Commonwealth University (VCU) institutional review board (IRB) waived the need for informed consent on all adult participants as samples were all archived and previously de-identified, with only VCU BMT clinical research staff retaining access to any patient specific information involved in the retrospective analysis
TraCS traverses through the genotypes of the called Single nucleotide polymorphisms (SNPs), systematically excluding identical SNPs or editing them to align with the graft-vs.-host (GVH) direction thereby generating a new variant call file (VCF) with SNPs for a particular donor-recipient pair (DRP) in the GVH direction (SNP present in the recipient, absent in the donor; R+/D−)
Summary
Graft-vs.-host Disease (GVHD) represents a significant cause of morbidity and mortality in stemcell transplant (SCT) recipients [1]. Clinical outcomes partially depend on the cumulative donor T cell responses to the burden of polymorphic recipient peptides Previous work applying this dynamical system model to HLA class I presented molecules demonstrates that there are large differences in the simulated T cell responses between different HLA matched DRP [21, 22]. In this hypothesis developing paper, previously reported findings of WES of SCT DRP are extended with an analysis of the HLA class II presentation of polymorphic peptides. This model may, in the future, permit successful simulation of alloreactive T cell responses between different donors and recipients in SCT
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