Project 2: Immunogenetics of Graft-versus-Host Disease (GVHD) The long-term goals of Project 2 are to improve the outcome of unrelated donor (URD) hematopoietic cell transplantation (HCT) for the treatment of hematopoietic malignancies and other blood disorders and broaden the availability of mismatched URD HCT through a better understanding of the immunogenetic basis of GVHD. We propose to re-define the transplantation barrier by introducing a novel DMAmicroarray technique to determine the physical linkage of HLA genes in unrelated donors and recipients. Project 2 will perform HLA haplotyping of donors and recipients to address the following aims: define the probability of identifying HLA allele-matched, haplotype-matched unrelated donors (Specific Aim 1);determine the extent to which matching for donor haplotypes can.reduce severe acute GVHD and improve survival after unrelated donor HCT (Specific Aim 2), and define locus- and haplotype-specific risks in unrelated HCT (Specific Aim 3). The risks conferred by single HLA-A, B, C, DRB1 or DQB1 mismatches will be determined in patients transplanted from donors matched for one haplotype. Single locus mismatches that are not associated with increased GVHD or lower survival may permit donor selection criteria to be relaxed and thereby enable more patients to benefit from transplantation. Among HLA allele-matched, haplotype-matched transplants, the risk of GVHD associated with the presence or absence of ancestral HLA haplotypes will be defined. Identification of GVHD-risk haplotypes will provide clinicians with a proxy for GVHD risk and will permit a focused strategy for laboratory-based GVHD mapping studies. The implications of this work to the overall theme of the Adult Leukemia Center Program Project are three-fold: 1) improve the safety of unrelated HCT by understanding the genetic basis of GVHD for donor selection;2) increase the availability of unrelated HCT by broadening the use of mismatched donors;and 3) increase the efficacy of unrelated HCT by understanding the genetic basis of graft-versus-leukemia. The aims outlined in this project will provide new information as to the influence of the MHC region in transplantation that will enable us to re-define the optimal alternative donor. Relevance to Public Health: We have developed a novel way to select unrelated donors for hematopoietic cell transplantation. In this project, we will test the effectiveness of this new selection technique in reducing the incidence and severity of graft-versus-host disease and other transplant complications, and in increasing the odds of finding an appropriate donor for patients in need.