Genetics of Graft-versus-Host Disease

异基因造血干细胞移植（allo-HSCT）是目前治疗许多晚期恶性肿瘤的唯一有效方法。 血液恶性肿瘤。allo-HSCT与显著的发病率和死亡率相关，主要是因为 移植物抗宿主病（GVHD）是由供体T细胞识别受体组织中存在的抗原引起的， 并引发同种免疫应答，导致对许多器官包括皮肤、胃肠道和肝脏的损伤 在收件人中。所有allo-HSCT接受者中超过一半发生不同程度的GVHD（I-IV级）。关于 20%的受体发展为严重的GVHD（III-IV级），这与非常高的发病率和死亡率相关。 决定移植物抗宿主病严重程度的最重要因素是供体和受体之间的遗传差异。 受体，如在用于供体选择的常规检查的HLA单倍型中所反映的。但即使捐赠者 并且受体是HLA-相同的，许多受体发展成严重的GVHD。结果，非HLA抗原被 急性GVHD的重要决定因素。移植物抗宿主病的一个有趣而独特的方面是 存在于一个个体中的抗原与另一个个体的免疫系统之间的相互作用。作为 结果供、受体基因型及其交互作用影响GVHD的发病。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 在3，000名接受allo-HSCT的患者及其各自供体（6，000名）中进行的关联研究（GWAS DNA样本），由国家骨髓捐献者计划（NMDP）和 国际血液和骨髓移植研究（CIBMTR）。我们的这部分资助是由中心批准的 用于遗传病研究（CIDR），并将在他们的测序设施中进行。我们预计将有3000人 受体将被分为1200例中度至重度急性GVHD（II-IV级）和1800例 无至轻度GVHD（0-I级）的个体。我们还将纳入现有的GWAS和临床结局 从两项先前研究中获得的7047对供体/受体的数据，以增加我们的队列 2830对II-IV级GVHD和4244对0-I级GVHD，并研究了GVHD和GVHD之间的相关性。 急性GVHD的严重程度和供体或受体的基因型，或某些基因型（除 HLA）的抗体。在第二个目标中，我们将验证在目标1中检测到的高危基因型与 1，750名供体和1，750名allo-HSCT受者的重度GVHD，并与 发现样本（估计4730对II-IV级与7094对0-I级GVHD）。我们将 确定了5000个单核苷酸多态性（SNP）的频率，目的1中的GWAS显示为 并将其与GVHD的严重程度相关联。在第三个目标中，我们将研究 检测到的SNP的功能效应与急性GVHD的严重程度显著相关 在混合淋巴细胞反应（MLR）中，作为同种免疫应答的离体替代物。

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.