Immunogenetics of Graft-Versus-Host Disease

移植物抗宿主病的免疫遗传学

• 批准号: 8277818
• 负责人: Effie W Petersdorf
• 金额: $ 37.96万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277818
• 关键词: Acute Graft Versus Host Disease; Address; Alleles; Cell Transplantation; Confidence Intervals; DNA; Data; Donor Selection; Donor person; Effectiveness; Genes; Genetic; Genetic Variation; Genomics; Goals; HLA-A gene; HLA-B Antigens; HLA-DR Antigens; Haplotypes; Hematological Disease; Hematopoietic; Hematopoietic Neoplasms; Histocompatibility; Histocompatibility Antigens; Human; Immune system; Immunogenetics; Incentives; Incidence; Individual; Laboratories; Link; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Maps; Methods; Molecular; Outcome; Patients; Probability; Proxy; Public Health; Registries; Relapse; Research; Research Personnel; Risk; Safety; Sampling; Selection Criteria; Severities; Stem cell transplant; Stratification; Surrogate Markers; Techniques; Technology; Testing; Time; Tissue Grafts; Transplantation; Variant; Work; adult leukemia; base; disorder prevention; disorder risk; graft vs host disease; hazard; high risk; human leukocyte antigen gene; improved; leukemia; mortality; novel; novel strategies; programs

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 cell transplantation (HCT) for the treatment of hematopoietic malignancies and other blood disorders and broaden the availability of mismatched URD HCT through a better understanding of the immunogenetic basis of GVHD. We propose to re-define the transplantation barrier by introducing a novel DMAmicroarray technique to determine the physical linkage of HLA genes in unrelated donors and recipients. Project 2 will perform HLA haplotyping of donors and recipients to address the following aims: define the probability of identifying HLA allele-matched, haplotype-matched unrelated donors (Specific Aim 1); determine the extent to which matching for donor haplotypes can.reduce severe acute GVHD and improve survival after unrelated donor HCT (Specific Aim 2), and define locus- and haplotype-specific risks in unrelated HCT (Specific Aim 3). The risks conferred by single HLA-A, B, C, DRB1 or DQB1 mismatches will be determined in patients transplanted from donors matched for one haplotype. Single locus mismatches that are not associated with increased GVHD or lower survival may permit donor selection criteria to be relaxed and thereby enable more patients to benefit from transplantation. Among HLA allele-matched, haplotype-matched transplants, the risk of GVHD associated with the presence or absence of ancestral HLA haplotypes will be defined. Identification of GVHD-risk haplotypes will provide clinicians with a proxy for GVHD risk and will permit a focused strategy for laboratory-based GVHD mapping studies. The implications of this work to the overall theme of the Adult Leukemia Center Program Project are three-fold: 1) improve the safety of unrelated HCT by understanding the genetic basis of GVHD for donor selection; 2) increase the availability of unrelated HCT by broadening the use of mismatched donors; and 3) increase the efficacy of unrelated HCT by understanding the genetic basis of graft-versus-leukemia. The aims outlined in this project will provide new information as to the influence 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 hematopoietic cell transplantation. In this project, we will test the effectiveness of this new selection technique in reducing the incidence and severity of graft-versus-host disease and other transplant complications, and in increasing the odds of finding an appropriate donor for patients in need.

项目2：移植物抗宿主病（GVHD）的免疫遗传学 项目2的长期目标是改善无关供体（URD）造血细胞的结果 用于治疗造血恶性肿瘤和其他血液疾病的移植（HCT） 通过更好地理解免疫原性，扩大了不匹配的URD HCT的可用性 GVHD的基础。我们建议通过引入一种新型的Dmamicroarray来重新定义移植屏障 确定无关捐助者和接受者中HLA基因物理联系的技术。项目2将 执行捐助者和接受者的HLA单倍型来解决以下目的：定义的概率 识别HLA等位基因匹配的，单倍型匹配的无关供体（特定AIM 1）；确定程度 与供体单倍型的匹配可以降低严重的急性GVHD并提高无关后的存活率 供体HCT（特定目标2），并在无关的HCT中定义了基因座和单倍型特异性风险（特定目的 3）。单个HLA-A，B，C，DRB1或DQB1不匹配的风险将在患者中确定 从供体匹配的单倍型中移植。与与之相关的单个基因座不匹配 GVHD或较低的生存率可能允许放松捐助者选择标准，从而启用更多 患者从移植中受益。在HLA等位基因匹配的，单倍型匹配的移植中，风险 将定义与祖先HLA单倍型的存在或不存在有关的GVHD。鉴别 GVHD风险的单型将为临床医生提供GVHD风险的代理，并将允许集中策略 用于实验室的GVHD映射研究。这项工作对成人的整体主题的含义 白血病中心计划项目分为三个：1）通过理解提高无关HCT的安全性 供体选择的GVHD的遗传基础； 2）通过扩展增加无关HCT的可用性 使用不匹配的捐助者； 3）通过了解遗传来提高无关HCT的疗效 移植物与白血病的基础。该项目概述的目的将提供有关该项目的新信息 MHC区域在移植中的影响，这将使我们能够重新定义最佳替代供体。 与公共卫生的相关性：我们已经开发了一种新颖的方式来为造血选择无关的供体 细胞移植。在这个项目中，我们将测试这种新选择技术在降低的有效性 移植物抗宿主疾病和其他移植并发症的发生率和严重程度，并增加 为有需要的患者找到合适的供体的几率。