Genetic Basis for KIR Effects in Hematopoietic Cell Transplantation

多种多态性杀伤细胞免疫球蛋白样受体（KIR）与高度多态性HLA相互作用 I类配体来调节自然杀伤（NK）细胞的发育和效应子功能。KIR基因 人类19号染色体上的一个家族在基因内容和等位基因多态性方面存在差异， 单倍型的形式：A和B，它们是KIR变异性的基本基础。我们已经证明了无关的 T细胞完全造血细胞移植治疗急性髓细胞白血病（AML）的结果 如果供体携带一种或两种KIR B单倍型，则移植显著改善。目标1 拟议的调查将进行遗传分析，并研究进一步的移植队列，以评估 B单倍型的端粒和着丝粒的一半对有益的移植结果的贡献，和 单个B单倍型特异性基因和等位基因的作用。目标2将是HLA I类 区分A和B KIR单倍型的各种KIR同种型和同种异型的特异性和亲合力， 重点是B特异性KIR。该分析将使用最近开发的结合测定法， 灵敏度和可靠性比以前使用的检测，并将检查全范围的HLA I类变异。 将使用细胞毒性的体外试验检测阳性结合反应的功能效应，其中单一定义的KIR变体与单一定义的HLA I类变体相互作用。还将检查确定的KIR组合。将使用来自功能分析的结果来开发更明智的和新的假设，这些假设将通过对目标1中研究的>1000例AML移植的队列的进一步回顾性分析来检验。因此，调查的进展将合乎逻辑地从床边转移到长凳上，然后再回到床边。本项目将确定A和B单倍型KIR之间的功能差异，并确定这些因素中哪些因素有助于B单倍型在急性髓性白血病移植中的生命增强效应。这些结果将改善潜在移植供体的遗传评估，从而改善危及生命的白血病的治疗性移植的结果。

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.