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: 6350214
• 负责人: Effie W Petersdorf
• 金额: $ 11.37万
• 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/6350214
• 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.

恶性血液病患者可通过无关供体治愈 (URD)骨髓移植。与从亲缘关系移植 然而，供者的URD移植与风险增加有关。 包括急性和慢性移植物抗宿主病在内的并发症 (GVHD)，移植物衰竭，以及需要长期免疫抑制。 近年来，临床研究证实了人类白细胞抗原基因的重要性。 在影响移植结果方面。捐赠者和受赠者的匹配 II基因人类白细胞抗原DRB1可降低急性移植物抗宿主病的风险，提高存活率。 然而，人类白细胞抗原-A、B和C类基因的不匹配会增加 移植失败的风险。除了经典的人类白细胞抗原基因，差异 因为其他基因可能会增加并发症的风险。 由于人类白细胞抗原-A、B、C、DRB和DQB1在基因上与URD患者相匹配 仍然患有移植物抗宿主病，并经历移植物失败。因为 MHC-I类分子及其相关分子在抗原中的基础作用 呈递和T细胞识别、人类白细胞抗原E和MIC具有即刻意义 临床移植环境中的免疫学兴趣。整体而言 这个项目的目标是确定URD骨髓的程度 移植可以通过更完整的供受者来优化 MHC区基因的匹配。基于PCR的技术将被开发为 序列分析：人类白细胞抗原E和最低抑菌浓度(特异靶L)。多态的程度， 等位基因在单倍型上的关联性和错配程度 将确定URD移植对中的HL A-E和-MIC等位基因 (具体目标2)。最后，错配对人类白细胞抗原E和MIC的影响 GVHD发生、移植失败和术后存活的等位基因 将研究骨髓移植(具体目标3)。这些研究 在本申请中提出的建议将提供重要的新信息 关于免疫中第I类区域基因的生物学相关性 应对并提供新的方法，以改善总体成果 骨髓移植。