Hematopoietic Stem Cell And Cord Blood Transplantation

PROJECT SUMMARY/ABSTRACT Hematopoietic cell transplantation (HCT) can cure life-threatening blood disorders; however, relapse remains the major obstacle. The advent of improved GVHD prevention regimens has increased the safety and availability of haploidentical related and multi-locus mismatched unrelated donors when matched donors are not available. The broadened availability of stem cell sources is a particular need of patients from diverse racial and ethnic backgrounds who often have fewer donor options. Although the safety and availability of HCT are improving, a major unmet need is to lower post-transplant relapse and increase survival through a more complete understanding of the role of HLA class I genes in relapse, and a means to apply the research findings to clinical care. We have identified sequence features of HLA-B leader peptides and of HLA-E ligand and its NK receptor repertoire in relapse and mortality. The discovery that leader peptides provide a means to identify permissive HLA mismatches, and inform the biology of HLA-E-associated relapse, is a new paradigm in HCT. The contributions of haplotype-linked HLA-A, -C and -G are unknown. We propose to define the role of HLA-A and -C leaders in permissive mismatches, and interactions between HLA-A and -C ligands and the ILT2 receptor. We hypothesize that HLA-G together with ILT2 inform relapse. Mechanisms for HLA-E and NKG2 receptors provide new information on the immunobiology of HCT. The specific aims are to: identify novel class I determinants of relapse and mortality, define the role of HLA and NK receptor variants in transplant outcome, and design tools to translate class I features into clinical practice. The goals will be achieved through systemic analysis of variation of classical and non-classical loci and associated receptors in large ethnically diverse transplant populations with complete clinical data. This proposal will fill the knowledge gap in the immunobiological basis of relapse and survivorship in HCT. The information will increase the safety, efficacy and availability of HCT for all patients in need of this life-saving therapy.