OPTIMIZING BMT FOR CANCER BY GENETIC MATCHING OF DONORS

通过捐赠者基因匹配优化癌症 BMT

• 批准号: 6628273
• 负责人: Effie W Petersdorf
• 金额: $ 12.06万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628273
• 关键词: MHC class I antigen; MHC class II antigen; T lymphocyte; alleles; antigen presentation; bone marrow transplantation; chemical association; clinical research; computer assisted sequence analysis; genetic polymorphism; genotype; graft versus host disease; haploidy; histocompatibility; histocompatibility gene; histocompatibility typing; homologous transplantation; human mortality; human subject; immune tolerance /unresponsiveness; isoantigen; major histocompatibility complex; neoplasm /cancer transplantation; polymerase chain reaction; transplantation immunology

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.

血液系统恶性肿瘤患者可以通过非亲缘供者治愈 (URD)骨髓移植与相关移植相比， 然而，URD移植与增加的风险有关。 包括急性和慢性移植物抗宿主病的并发症 移植物抗宿主病（GVHD），移植失败，需要长期免疫抑制。 近年来，临床研究证实了HLA基因的重要性 影响移植结果。类的供体-受体匹配 II基因HLA-DRB 1降低急性GVHD的风险并提高生存率， 而I类基因HLA-A、B和C的错配增加了 移植失败的风险。除了经典的HLA基因外， 因为其他基因可能会增加并发症的风险 由于HLA-A、B、C、DR B和DQB 1基因型匹配URD受体 仍然发展为GVHD并经历移植失败。因为 MHC I类及相关分子在抗原中的基本作用 HLA-E和MIC的表达与T细胞的识别密切相关。 在临床移植环境中的免疫学兴趣。整体 该项目的目标是确定URD骨髓 移植可以通过更完整的供体-受体来优化， MHC区域基因的匹配。将开发基于PCR的技术， 序列HLA-E和MIC（特异性目标1）。多态性的程度， 单倍型上等位基因的关联和错配程度， 将确定URD移植对中的HLA-E和-MIC等位基因 （具体目标2）。最后，研究了HLA-E和MIC错配的影响。 等位基因对GVHD的发展、移植失败和移植后存活的影响 将研究骨髓移植（具体目标3）。研究 本申请中提出的建议将提供重要的新信息 关于I类区域基因在免疫系统中的生物学相关性， 提出新的办法，以改善 骨髓移植