Immuno and Epigenetics of Hematopoietic Cell Transplantation

PROJECT SUMMARY/ABSTRACT Hematopoietic cell transplantation from related and unrelated donors can cure life-threatening blood disorders; however, graft-versus-host disease (GVHD) and relapse remain the major obstacles. When matched donors are not available, the properties of that govern (un)favorable HLA mismatches are not well-defined. These deficiencies have important implications for a large fraction of patients who lack HLA-matched donors, and for all patients at risk for disease relapse. The advent of improved GVHD prevention regimens has increased the safety and efficacy of haploidentical transplantation and it is anticipated that its use in multi-locus mismatched unrelated transplantation will substantially increase options for patients. The unmet needs are to understand the mechanisms through which HLA-DR and -DQ genes modulate transplant risks, and a means to apply the research findings to clinical care. We have recently identified important features of HLA-DQ molecules and HLA-DR expression that describe (un)favorable mismatches, and they represent an entirely new paradigm for the HLA class II region. We propose to define the underlying mechanisms through which matched and mismatched HLA-DR and -DQ function in transplantation. The specific aims are to: determine the role of HLA- DQ structure and expression in outcome; determine the role of HLA-DRβ molecules in outcome; determine the impact of HLA-DR-DQ haplotype variation on clinical outcome after HLA-matched and -mismatched allogeneic transplantation, and design tools to translate class II features into clinical practice. The goals will be achieved through systemic analysis of HLA-DR and -DQ variation, peptide repertoire and expression in large ethnically diverse transplant populations with complete clinical data. This proposal will fill the knowledge gap in the immunobiological basis of GVHD, relapse and survivorship in transplantation. The information will increase the safety, efficacy and availability of transplantation for all patients in need of this life-saving therapy.