Immunogenetics of Graft-Versus-Host Disease

项目2：移植物抗宿主病(GVHD)的免疫遗传学 项目2的长期目标是改善非血缘供者(URD)造血细胞的结果 移植(HCT)治疗恶性血液病和其他血液疾病 通过更好地了解免疫遗传学，扩大不匹配URD Hct的可用性 GVHD的基础。我们建议通过引入一种新的DNA微阵列来重新定义移植障碍 无血缘关系的供受者中确定人类白细胞抗原基因物理连锁的技术。项目2将 对捐献者和接受者进行人类白细胞抗原单倍型分析，以达到以下目标：确定 确定HLA等位基因匹配、单倍型匹配的无血缘关系捐赠者(特定目标1)；确定程度 供者单倍型配型可减少严重急性移植物抗宿主病并提高非亲缘关系移植后的存活率。 捐献者红细胞压积(特定目标2)，并确定无关红细胞压积的基因座和单倍型特有风险(特定目标 3)。单一的HLA-A、B、C、DRB1或DQB1错配所带来的风险将在患者中确定 从一个单倍型匹配的捐赠者身上移植的。与不关联的单基因座不匹配 增加GVHD或降低存活率可能允许放宽捐赠者选择标准，从而实现更多 患者将从移植中受益。在HLA等位基因匹配、单倍型匹配的移植中，风险 将定义与祖先存在或不存在人类白细胞抗原单倍型相关的移植物抗宿主病。鉴定 GVHD风险单倍型将为临床医生提供GVHD风险的替代指标，并将允许有针对性的策略 用于以实验室为基础的GVHD图谱研究。这部作品对《成年人》总体主题的影响 白血病中心计划项目有三个方面：1)通过了解提高无关HCT的安全性 移植物抗宿主病用于供者选择的遗传基础；2)通过扩大范围增加无关的血细胞移植的可用性 使用不匹配的供者；以及3)通过了解遗传基因来提高无关HCT的疗效 移植物抗白血病的基础。本项目中概述的目标将提供有关 MHC区域对移植的影响，这将使我们能够重新定义最佳的替代供体。 与公共健康的相关性：我们已经开发出一种新的方法来选择无关的捐赠者进行造血 细胞移植。在这个项目中，我们将测试这种新的选择技术在减少 移植物抗宿主病和其他移植并发症的发生率和严重性，并在不断增加 为有需要的病人找到合适捐赠者的几率。

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.