Immuno and Epigenetics of Hematopoietic Cell Transplantation

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HLA-matched and mismatched related and unrelated donor hematopoietic cell transplantation can cure life-threatening blood disorders. The unmet needs of patients are to identify the optimal transplant donor, and to lower risks of acute and chronic graft-versus-host disease (GVHD), relapse and mortality. We recently discovered that the level of expression of HLA-C and HLA- DP allotypes defines (non)permissive mismatches. Patient mismatching for high-expression allotypes is associated with high risks of GVHD and mortality compared to low-expression allotypes and should be avoided where possible. In HLA-A,B,C,DR,DQ,DP-matched unrelated donor transplantation, possession of high-expression HLA-DP allotypes is associated with high risk of GVHD compared to no high-expression allotypes. These data firmly demonstrate that the amount of HLA protein is as important as the kind of HLA protein. We have convincing data that HLA-DR and DQ expression is allotype-specific. We propose that HLA-matched and mismatched related and unrelated transplantation can be improved with knowledge of HLA-DR and DQ expression. The specific aims are to: determine HLA-DR and DQ allotype and haplotype-specific expression; define the 5’, coding, 3’ and XL9 region variants for diverse DR- DQ alleles; relate regulatory sequence variation to expression, and define the clinical significance of DR/DQ expression in matched and mismatched transplantation. This proposal will fill the knowledge gap in the HLA barrier as defined by expression. The information will increase the safety, efficacy and availability of transplantation for patients in need of this life- saving therapy.