POLYMORPHISM AND TRANSPLANTATION BIOLOGY OF HLA RESIDENT GENES

这个应用程序的长期目标是调查 非人类白细胞抗原-A、B、C基因与非血缘关系供者骨髓结局的关系 移植。尽管经典I类抗原的基因匹配 显然是骨髓移植成功的主要决定因素， 供者移植物抗宿主病(GVHD)发生率的比较 相关移植与在非相关移植中观察到的结果显示 一定还有其他多态遗传因素参与其中。我们想要 检验存在非人类白细胞抗原-A、B、C基因的假设 主要组织相容性复合体(MHC)内的组件 与经典的I类抗原没有连锁不平衡， 因此，在很大比例的不相关的 骨髓移植。我们将进一步检查这种基因是否 差异是造成观察到的GVHD差异的原因。为了 验证这个假设，我们已经克隆了跨越整个I类区域的 包括所有I类基因在内的近240万个碱基对。拥有 克隆的整个I类区域使得识别几个 新一类将基因联系在一起。因此，有可能检查 最多态基因座的功能特征和随后的 他们在移植结果中的潜在参与。我们之前的工作是 提供了两个符合以下标准的非人类白细胞抗原-A、B、C基因实例 表现出与人类白细胞抗原不连锁不平衡的多态 经典I类，分别为HLAE和MICA。因此，在人类白细胞抗原-A、-B中 匹配的非亲缘移植，人类白细胞抗原E不匹配的可能性是 高，云母不匹配的可能性更高。具体目标是 阐明人类白细胞抗原I类区域的大规模基因组多样性和 鉴定和鉴定特异蛋白的结构和表达 位于第I类区域内的多态基因。我们将使用这个 研究其他多态基因参与的信息 而不是骨髓移植中的人类白细胞抗原-A、B、C。这将通过定义 并测量多态程度和相关多态 在不相关的人类白细胞抗原相合移植中的移植结果。我们会 也检查MHC居民的多态部分的可能性 蛋白质将由经典类提出。一种新的蛋白质的识别 MHC中的多态基因座为研究提供了新的可能性 无血缘关系的供受者对中发生移植物抗宿主病的基础。 与MHC相关的遗传因素被假设为影响 对异基因骨髓的免疫反应，但它们的定义仍然存在 难以捉摸。我们现在准备确定这些基因座并彻底探索 他们可能参与了一个无关骨髓的结果 移植。

The long range goals of this application are to investigate the role of non HLA-A, B, C genes in the outcome of an unrelated donor marrow transplant. Although genetic matching of the classical class I antigens is clearly a major determinant of successful marrow transplant outcome, comparisons of the frequency of graft versus host disease (GVHD) in donor related transplants with that observed in unrelated transplants has shown that other polymorphic genetic factors must be involved. We would like to test the hypothesis that there exist non HLA-A, B, C genetic components within the major histocompatibility complex (MHC) which are not in linkage disequilibrium with the classical class I antigens and which consequently are mismatched in a large percentage of unrelated marrow transplants. We will further examine whether this genetic difference contributes to the observed difference in GVHD. In order to test this hypothesis, we have cloned the entire class I region spanning nearly 2.4 million base pairs including all of the class I genes. Having the entire class I region cloned has made it feasible to identify several new class I linked genes. Therefore it will be possible to examine the functional characteristics of the most polymorphic loci and subsequently their potential involvement in transplant outcome. Our previous work has provided two examples of non-HLA-A, B, C genes which fit the criteria of exhibiting polymorphism which is not in linkage disequilibrium with HLA classical class I, those being HLA-E and MICA. Thus, in an HLA-A, -B matched unrelated transplant, the likelihood of an HLA-E mismatched is high and of MICA being mismatched even higher. The specific aims are to elucidate the large scale genomic diversity of the HLA class I region and to identify and characterize the structure and expression of specific polymorphic genes resident within the class I region. We will use this information to investigate the involvement of polymorphic genes other than HLA-A, B, C in a marrow transplant. This will be done by defining and measuring the extent of polymorphism and correlating polymorphism with transplant outcome in unrelated HLA identical transplants. We will also examine the potential for polymorphic portions of MHC resident proteins to be presented by classical class I. The recognition of a new polymorphic locus in the MHC presents new possibilities for investigating the basis for GVHD in HLA-matched unrelated donor-recipient pairs. Genetic factors related to the MHC have been postulated to influence the immune response to allogeneic marrow, but their definition has remained elusive. We are now poised to identify such loci and thoroughly explore their potential involvement in the outcome of an unrelated marrow transplant.