Worldwide clinical experience has demonstrated the role for unrelated donor hematopoietic cell transplantation as a curative modality for hematologic malignancies. DNA-based methods have been applied to match class I HLA-A, B, C and class II HLA-DRB1, DQB1, DPB1 alleles of the donor as a surrogate for matching for donor haplotypes. Despite complete allele identity, matched unrelated donor transplantation has higher rates of graft failure, GVHD and mortality compared to genotypically matched sibling and haploidentical related transplants. We hypothesize that HLA allele-matched unrelated donors are mismatched for donor haplotypes and that undetected disparities that are encoded on these haplotypes can confer increased post-transplant complications including acute and chronic GVHD and mortality. We also hypothesize that patients who are matched for both donor haplotypes have improved clinical outcome compared to patients who share no haplotype with their donor. We have developed an array-based method for determining the two extended HLA haplotypes in the donor. Genomic DNA is allowed to hybridize to an HLA-B-specific oligonucleotide probe to separate the two haplotypes. The DNA is extracted and the haplotype is typed for the remaining class I and II genes. In this study, we propose to develop and refine our haplotyping approach to determine the biological significance of donor haplotype matching as a means for improving clinical outcome after transplantation. We will develop and refine our array-based haplotype method (Specific Aim 1) and determine the extent to which clinical outcome in HLA allele-matched (Specific Aim 2) and HLA mismatched (Specific Aim 3) transplantation is improved by matching donor haplotypes. We will characterize microsatellite markers in our study population as a means to refine mapping of MHC SNPs that confer biological importance in hematopoietic cell transplantation (Specific Aim 4). This work has immediate practical implications in clinical transplantation: a novel genetic approach to improve clinical outcome; a strategy for donor recruitment, determination of registry size and composition, and new information on MHC-encoded polymorphisms that function as transplantation determinants.
Showing the most recent 10 out of 37 publications
