Genetic Basis for KIR Effects in Hematopoietic Cell Transplantation

多样性和多态的杀伤细胞免疫球蛋白样受体(KIR)与高度多态的人类白细胞抗原相互作用 I类配体调节自然杀伤(NK)细胞的发育和效应功能。KIR基因 人类19号染色体上的家族在基因含量和等位基因多态方面存在差异，从而使两个 单倍型的形式：A和B，这是KIR可变性的基本基础。我们已经展示了无关的 T细胞全造血细胞移植治疗急性髓系白血病 如果供者携带一种或两种KIR B单倍型，移植效果会显著改善。目标1 拟议的调查将进行遗传分析，并研究更多的移植队列，以评估 B单倍型的端粒和着丝粒部分对有益的移植结果的贡献，以及 个体B单倍型特异性基因和等位基因的作用。AIM 2将与HLAI类进行比较 区分A和B KIR单倍型的各种KIR同工型和同种异型的特异性和亲和力 重点是B-特定的KIR。这项分析将使用一种最近开发的结合分析，这种结合分析明显比 比以前使用的检测方法更灵敏和可靠，并将检查所有HLAI类变异。 阳性结合反应的功能效应将通过体外细胞毒性试验进行测试，在该试验中，单个定义的KIR变体与单个定义的HLAI类变体相互作用。还将研究KIR的定义组合。功能分析的结果将被用来开发更多的知情和新的假设，这些假设将通过对目标1中研究的1000例急性髓细胞白血病移植患者的进一步回顾分析来检验。因此，从逻辑上讲，研究的进展将从床边转移到工作台，然后回到床边。该项目将确定A和B单倍型KIR之间的功能差异，并确定这些因素中的哪些因素有助于B单倍型在急性髓系白血病移植中提高生命的效果。这一结果将完善对潜在移植捐赠者的基因评估，从而改善威胁生命的白血病治疗性移植的结果。

Diverse and polymorphic killer cell immunoglobulin-like receptors (KIR) interact with highly polymorphic HLA class I ligands to regulate the development and effector functions of natural killer (NK) cells. The KIR gene family on human chromosome 19 varies In gene content and allelic polymorphism to give two distinctive forms of haplotype: A and B, that are the fundamental basis of KIR variability. We have shown for unrelated T-cell replete hematopoietic cell transplantations for acute myelogenous leukemia (AML) that the outcome of transplantation is significantly improved if the donor carries one or two KIR B haplotypes. Aim 1 ofthe proposed investigation will perform genetic analysis, and study of further transplant cohorts, to assess the contribution of the telomeric and centromeric halves of the B haplotype to beneficial transplant outcome, and the role of the individual B haplotype specific genes and alleles. Aim 2 will comJDare the HLA class I specificity and avidity of the various KIR isotypes and allotypes that distinguish A and B KIR haplotypes, with emphasis on B-specific KIR. This analysis will use a recently developed binding assay that is markedly more sensitive and reliable than previously used assays, and will examine the full range of HLA class I variation. The functional effects of positive binding reactions will be tested using an in vitro assay of cellular cytotoxicity in which single defined KIR variant interacts with a single defined HLA class I variant. Defined combinations of KIR will also be examined. The results from the functional analysis will be used, to develop rnore informed and new hypotheses, that will be tested by further retrospective analysis of the cohort of >1000 AML transplants studied in Aim 1. Thus the progress of investigation will logically move from bedside to bench and then back to bedside. This project will determine functional differences between the A and B haplotype KIR and determine which of these factors contribute to life-enhancing effect ofthe B haplotype in transplantation for acute myelogenous leukemia. The results should refine the genetic assessment of potential donors for transplantation, and thus improve the outcome of life-saying therapeutic transplantation for life-threatening leukemia.