Genetics of Graft-versus-Host Disease

移植物抗宿主病的遗传学

• 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
• 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

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.

同种异体造血干细胞移植（Allo-HSCT）是许多晚期治疗的唯一治疗疗法 血液学恶性肿瘤。 Allo-HSCT与重大病因和死亡率有关，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）， 并发起同种免疫反应，导致对包括皮肤，胃肠道和肝脏在内的许多器官的损害 在收件人中。在所有Allo-HSCT接受者中，超过一半会产生不同程度的GVHD（I-IV级）。关于 20％的接受者会出现严重的GVHD（III-IV级），这与非常高的发病率和死亡率有关。 确定GVHD严重程度的最重要因素是捐赠者和 接受者，正常检查供体选择的HLA单倍型反映。但是即使捐助者 接收者是HLA，许多接受者都会发展出严重的GVHD。结果，非HLA抗原是 急性GVHD的重要决定因素。 GVHD的一个有趣而独特的方面是结果 一个人与另一个人的免疫系统存在的抗原之间的相互作用。作为 结果，供体和受体的基因型及其相互作用会影响GVHD的发病机理。到 确定GVHD的遗传风险因素，在第一个目标（发现阶段），我们将进行全基因组 协会研究（GWAS）对3,000例接受Allo-HSCT及其各自捐助者的患者（6000例） 由国家骨髓供体计划（NMDP）和中心提供给我们的DNA样本） 国际血液和骨髓移植研究（CIBMTR）。我们赠款的这一部分已获得中心批准 用于遗传性疾病研究（CIDR），并将在其测序设施中进行。我们希望3000 接收者将分为1200名，中度至重度急性GVHD（II-IV级）与1800 没有轻度GVHD的人（0-I级）。我们还将包括现有的GWA和临床结果 关于7047个捐助者/收件人对的数据，可从前两项研究，以增强我们的队列，并估计 2830对II-IV级和4244对与0-I级GVHD对，并研究 供体或受体中急性GVHD和基因型的严重程度，或某些基因型不匹配（除了 HLA）。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名捐助者和1,750名Allo-HSCT的严重GVHD，并与 发现样品（估计有4730对II-IV级与7094对，具有0-I级GVHD）。我们将 确定5000个单核苷酸多态性（SNP）的频率，AIM 1中的GWAS显示为 与严重的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的功能效应与急性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离体替代物。