Genetics of Graft-versus-Host Disease

异基因造血干细胞移植(allo-hsct)是许多晚期疾病的唯一治疗方法。 恶性血液病。ALLO-HSCT与显著的发病率和死亡率有关，主要是因为 移植物抗宿主病(GVHD)是由供者T细胞识别受体组织中存在的抗原引起的， 启动同种异体免疫反应，导致包括皮肤、胃肠道和肝脏在内的许多器官受损 在收件人中。超过一半的allo-HSCT受者发展为不同程度的移植物抗宿主病(I-IV级)。关于 20%的受者发生严重的GVHD(III-IV级)，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 受体，正如在常规检查供体选择的HLA单倍型中所反映的那样。但即使捐赠者 而且受者的人类白细胞抗原相合，许多受者发展成严重的移植物抗宿主病。因此，非人类白细胞抗原是 急性移植物抗宿主病的重要决定因素。GVHD有趣而独特的一个方面是，它是 一个人体内的抗原与另一个人的免疫系统之间的相互作用。作为一名 结果供受者的基因分型及其交互作用影响GVHD的发病。至 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 3000名接受allo-HSCT的患者及其各自供者(6000人)的关联研究 DNA样本)，由国家骨髓捐赠者计划(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)，并将在其测序设施中进行。我们预计3000人 受者将被分成1200名患有中到重度急性移植物抗宿主病(II-IV级)的受试者，而不是1800名 无至轻度移植物抗宿主病(0-I级)的个体。我们还将包括现有的GWAS和临床结果 来自之前两项研究的7047对捐赠者/受赠者的数据，以增加我们的队列估计 2830对II-IV级和4244对0-I级GVHD，并调查 供者或受者急性移植物抗宿主病的严重程度和基因类型，或某些基因类型不匹配(除 Hla)。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与 1,750例allo-HSCT供者和1,750例受者中的严重GVHD，并与 发现样本(估计有4730对II-IV级GVHD对7094对0-I GVHD)。我们会 确定目标1中显示的5000个单核苷酸多态(SNP)的频率 与严重移植物抗宿主病相关，并与移植物抗宿主病的严重程度相关。在第三个目标中，我们将调查 SNPs的功能效应与急性移植物抗宿主病的严重程度显著相关 在混合淋巴细胞反应(MLR)中，作为同种异体免疫反应的体外替代品。

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.