Genetics of Graft-versus-Host Disease

移植物抗宿主病的遗传学

基本信息

批准号：
10215440
负责人：
Vahid Afshar-Kharghan
金额：
$ 28.15万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-08 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215440
关键词：
Acute Graft Versus Host Disease Affect Allogenic Antigens Applications Grants Biological Biological Assay Blood Blood Cells Blood donor Bone Marrow Bone Marrow Transplantation Clinical Clinical Data DNA Data Disease Donor Selection Fred Hutchinson Cancer Research Center Frequencies Gastrointestinal tract structure Genetic Genotype Goals Grant Haplotypes Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Hereditary Disease High Dose Chemotherapy Human Immune Immune response Immune system In Vitro Incidence Individual Joints Liver Marrow Mixed Lymphocyte Culture Test Morbidity - disease rate Organ Outcome Pathogenesis Patients Phase Preparation Research Role Sampling Severities Single Nucleotide Polymorphism Skin T-Lymphocyte Tissues Transplantation Validation bead chip cohort curative treatments donor stem cell effective therapy genetic risk factor genetic variant genome wide association study genome-wide graft vs host disease high risk improved international center mortality peripheral blood programs response risk variant stem cells

项目摘要

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for many advanced hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues, and initiating an alloimmune response resulting in damage to many organs including the skin, GI tract, and liver in recipient. More than half of all allo-HSCT recipients develop different degrees of GVHD (grade I-IV). About 20% of recipients develop severe GVHD (grade III-IV) that is associated with a very high morbidity and mortality. The most important factor determining the severity of GVHD is the genetic disparities between donors and recipients, as is reflected in HLA haplotypes that are routinely checked for donor selection. But even when donors and recipients are HLA-identical many recipients develop severe GVHD. As a result, non-HLA antigens are important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence of an interaction between antigens present in one individual with the immune system of another individual. As a result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide Association Studies (GWAS) in 3,000 patients who underwent allo-HSCT and in their respective donors (6000 DNA samples) that are provided to us by the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research (CIBMTR). This part of our grant is approved by the Center for Inherited Disease Research (CIDR) and will be conducted in their sequencing facility. We expect that 3000 recipients will be stratified into 1200 subjects with moderate to severe acute GVHD (grades II-IV) versus 1800 individuals with none to mild GVHD (grade 0-I). We will also include the existing GWAS and clinical outcome data on 7047 donor/recipient pairs available from two previous studies to augment our cohort with an estimated 2830 pairs with grade II-IV and 4244 pairs with grade 0-I GVHD, and investigate an association between the severity of acute GVHD and genotypes in donors or recipients, or mismatch of certain genotypes (other than HLA). In the second aim, we will validate the association between high risk genotypes detected in the aim 1 and severe GVHD in 1,750 donors and 1,750 recipients of allo-HSCT, and perform the joint analysis with the discovery samples (an estimated 4730 pairs with grade II-IV vs 7094 pairs with Grade 0-I GVHD). We will determine the frequency of 5000 single nucleotide polymorphisms (SNP), that GWAS in the aim 1 showed to be associated with severe GVHD and correlate it to the severity of GVHD. In the third aim, we will investigate the functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD in mixed lymphocyte reaction (MLR), as an Ex vivo surrogate for an alloimmune response.

异基因造血干细胞移植（allo-HSCT）是许多晚期患者唯一的治疗方法血液系统恶性肿瘤。 Allo-HSCT 与显着的发病率和死亡率相关，主要是因为由供体 T 细胞识别受体组织中存在的抗原引起的移植物抗宿主病 (GVHD)，并启动同种免疫反应，导致许多器官受损，包括皮肤、胃肠道和肝脏在收件人中。超过一半的异基因造血干细胞移植接受者出现不同程度的 GVHD（I-IV 级）。关于 20% 的接受者出现严重的 GVHD（III-IV 级），这与非常高的发病率和死亡率相关。决定GVHD严重程度的最重要因素是捐赠者和捐赠者之间的遗传差异。受体，正如在供体选择时常规检查的 HLA 单倍型中所反映的那样。但即使捐赠者且受者的 HLA 相同，许多受者会出现严重的 GVHD。因此，非 HLA 抗原急性 GVHD 的重要决定因素。 GVHD 的一个有趣且独特的方面是，它是一个个体中存在的抗原与另一个个体的免疫系统之间的相互作用。作为一个结果，供体和受体的基因型及其相互作用影响GVHD的发病机制。到确定GVHD的遗传风险因素，在第一个目标（发现阶段），我们将进行Genome-Wide 关联研究 (GWAS) 在 3,000 名接受异基因造血干细胞移植的患者及其各自的捐赠者 (6000 DNA 样本）由国家骨髓捐赠计划 (NMDP) 和中心提供给我们国际血液和骨髓移植研究 (CIBMTR)。我们的这部分补助金已获得中心批准用于遗传性疾病研究（CIDR），并将在他们的测序设施中进行。我们预计 3000 接受者将被分为 1200 名患有中度至重度急性 GVHD（II-IV 级）的受试者，而 1800 名受试者无或轻度 GVHD 的个体（0-I 级）。我们还将包括现有的 GWAS 和临床结果之前两项研究中提供了 7047 对捐赠者/接受者对的数据，以估计 2830对II-IV级GVHD和4244对0-I级GVHD，并调查了两者之间的关联急性 GVHD 的严重程度和供者或受者的基因型，或某些基因型不匹配（除了人类白细胞抗原）。在第二个目标中，我们将验证目标 1 中检测到的高风险基因型与 1,750名allo-HSCT供者和1,750名受者的严重GVHD，并与发现样本（估计有 4730 对 II-IV 级 GVHD，而 7094 对 0-I 级 GVHD）。我们将确定 5000 个单核苷酸多态性 (SNP) 的频率，目标 1 中的 GWAS 显示为与严重 GVHD 相关，并将其与 GVHD 的严重程度相关联。在第三个目标中，我们将调查检测和验证的 SNP 功能效应与急性 GVHD 的严重程度显着相关在混合淋巴细胞反应（MLR）中，作为同种免疫反应的体外替代物。