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 celltransplantation (HCT) for the treatment of hematopoietic malignancies and other blood disorders andbroaden the availability of mismatched URD HCT through a better understanding of the immunogeneticbasis of GVHD. We propose to re-define the transplantation barrier by introducing a novel DMAmicroarraytechnique to determine the physical linkage of HLA genes in unrelated donors and recipients. Project 2 willperform HLA haplotyping of donors and recipients to address the following aims: define the probability ofidentifying HLA allele-matched, haplotype-matched unrelated donors (Specific Aim 1); determine the extentto which matching for donor haplotypes can.reduce severe acute GVHD and improve survival after unrelateddonor HCT (Specific Aim 2), and define locus- and haplotype-specific risks in unrelated HCT (Specific Aim3). The risks conferred by single HLA-A, B, C, DRB1 or DQB1 mismatches will be determined in patientstransplanted from donors matched for one haplotype. Single locus mismatches that are not associated withincreased GVHD or lower survival may permit donor selection criteria to be relaxed and thereby enable morepatients to benefit from transplantation. Among HLA allele-matched, haplotype-matched transplants, the riskof GVHD associated with the presence or absence of ancestral HLA haplotypes will be defined. Identificationof GVHD-risk haplotypes will provide clinicians with a proxy for GVHD risk and will permit a focused strategyfor laboratory-based GVHD mapping studies. The implications of this work to the overall theme of the AdultLeukemia Center Program Project are three-fold: 1) improve the safety of unrelated HCT by understandingthe genetic basis of GVHD for donor selection; 2) increase the availability of unrelated HCT by broadeningthe use of mismatched donors; and 3) increase the efficacy of unrelated HCT by understanding the geneticbasis of graft-versus-leukemia.
The aims outlined in this project will provide new information as to theinfluence 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 hematopoieticcell transplantation. In this project, we will test the effectiveness of this new selection technique in reducingthe incidence and severity of graft-versus-host disease and other transplant complications, and in increasingthe odds of finding an appropriate donor for patients in need.
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