OPTIMIZING BMT FOR CANCER BY GENETIC MATCHING OF DONORS

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Patients with hematologic malignancies can be cured with unrelated donor (URD) marrow transplantation. Compared to transplantation from related donors, however, URD transplantation is associated with an increased risk of complications including acute and chronic graft-versus-host disease (GVHD), graft failure, and the need for prolonged immunosuppression. Recently, clinical studies have demonstrated the importance of HLA genes in influencing transplant outcome. Donor-recipient matching for the class II gene HLA-DRB1 reduces the risk of acute GVHD and improves survival, whereas mismatching for the class I genes HLA-A, B and C increases the risk of graft failure. In addition to the classical HLA genes, disparity for other genes may contribute to an increased risk of complications since HLA-A, B, C, DRB and DQB1 genotypically matched URD recipients still develop GVHD and experience graft failure. Because of the fundamental role of MHC class I and related molecules in antigen presentation and T cell recognition, HLA-E and MIC are of immediate immunological interest in the clinical transplant setting. The overall goal of this project is to determine the extent to which URD marrow transplantation can be optimized by more complete donor-recipient matching of MHC region genes. PCR-based technology will be developed to sequence HLA-E and MIC (Specific Aim l). The extent of polymorphism, the association of alleles on haplotypes and the degree of mismatching for HLA-E and-MIC alleles in URD transplant pairs will be determined (Specific Aim 2). Finally, the effect of mismatching for HLA-E and MIC alleles on the development of GVHD, graft failure and survival after marrow transplantation will be studied (Specific Aim 3). The studies proposed in this application will provide important new information concerning the biological relevance of class I region genes in the immune response and offer new approaches for improving the overall outcome of marrow transplantation.