NK Cells, Their Receptors and Unrelated Donor Transplant

描述(由申请人提供)：最近的T细胞耗竭半相合造血细胞移植(HCT)试验表明，当NK细胞没有受体KIR配体居住时，NK细胞的反应性可以减少GVHD，降低复发风险，并提高总体存活率。在明尼苏达大学的一组非血缘关系供者(URD)HCT受者中，没有看到生存优势，这表明临床环境或相关免疫学的其他组成部分的差异可能解释了这些不同的临床结果。本项目要检验的主要假设是，NK细胞在URD移植中具有生物学意义，杀伤免疫球蛋白样受体(KIR)与MHC 1类配体的相互作用可以改变临床结果。该计划包括一组NK细胞生物学和骨髓移植方面的国际专家，他们合作调查URD HCT中NK同种异体反应性的相关性，在这种情况下，KIR谱系在几乎所有的供受者对中都不同。我们将利用国家骨髓捐赠者计划(NMDP)提供的数千份血液和DNA样本，以及他们关于移植结果的高质量长期随访数据。项目1将侧重于捐赠者和受赠者之间固有的KIR差异的生理作用，使用从简单基因含量到单倍型组织的越来越高的KIR测定分辨率。这些研究将发现新的KIR等位基因多态，并将确定它们的临床意义。然而，在许多患者中，KIR在移植后不能正常表达。因此，在项目2，NK细胞的发展，功能性KIR的获得和决定KIR表达的机制将被研究。回溯性NMDP队列研究将促进项目1和项目2的即时床边到工作台研究。在项目3中，前瞻性试验将在临床上利用NK细胞的反应性，并在项目1和项目2的基础上促进对KIR基因型和KIR发展的前瞻性评估。此外，还将研究更高分辨率的KIR基因分型和配型对HCT后临床并发症风险的影响。所有项目之间的协同作用将把基础NK生物学从替补席带到蜜蜂身边，通过更好的供体选择、KIR谱系操作或促进NK细胞发育来改善URD HCT的结果。除了管理(A)和生物统计学(B)核心外，这些项目还得到科学核心的支持，每个核心都与KIR基因分型(核心C)、K.IR单倍型测序(核心D)和KIR序列公共数据库(核心E)的所有项目相结合。综上所述，这些高度集中和综合的研究vv11明确地评估了NK细胞及其受体在URD IICT中的作用，并扩大了替代供体移植的成功，这是许多晚期癌症患者唯一潜在的治愈方法。

DESCRIPTION (provided by applicant): Recent trials of T-cell depleted haploidentical hematopoeitic cell transplantation (HCT) suggest that NK cell reactivity can lead o less GVHD, reduced risks of relapse and improved overall survival when NK cells are NOT inhabited by recipient KIR ligands. In a cohort of Unrelated Donor (URD) HCT recipients at the University of Minnesota, no survival advantage was seen, suggesting that differences in clinical settings or other components of the relevant immunotiology may account for these disparate clinical results. The main hypothesis to be tested in this Program is that NK cells are of biologic importance in URD transplantation and that killer immunoglobulin-like receptor (KIR) interactions with MHC class 1 ligands can alter the clinical outcomes. This Program includes a group of international experts in NK cell biology and bone marrow transplantation collaborating to investigate the relevance of NK alloreactivity in URD HCT, a setting where KIR repertoires differ in nearly all donor-recipient pairs. We will utilize the many thousands of blood and DNA samples available through the National Marrow Donor Program (NMDP) and their high quality long-term follow-up data available on transplant outcomes. Project 1 will focus on the physiologic role of KIR differences inherent between donors and recipients using increasingly higher resolution of KIR determinations from simple gene content to haplotype organization. Novel KIR allele polymorphisms will be identified from these studies and their clinical significance will be determined. However, in many patients, KIR are not expressed normally after transplant. Therefore, in Project 2, NK cell development, the acquisition of functional KIR and the mechanisms that determine KIR expression will be studied. The retrospective NMDP cohort studies will facilitate immediate bedside to bench studies for Projects 1 and 2. In Project 3, prospective trials will exploit NK cell reactivity clinically and facilitate prospective evaluation of KIR genotype and KIR development based upon the work of Projects 1 and 2. Additionally, higher resolution KIR genotyping and matching will be studied for their impact on the risks of clinical complications after HCT. The synergistic interaction between all projects will take basic NK biology from the bench to the bee side to improve outcomes of URD HCT by better donor selection, KIR repertoire manipulation or enhancement of NK cell development. In addition to Administration (A) and Biostatistics (B) Cores, the projects are supported by scientific cores, each integrating with all projects for KIR genotyping (Core C), K.IR haplotype sequencing (Core D) and a KIR sequence public database (Core E). Taken together, these highly focused and integrated studies vv 11 definitively assess the role of NK cells and their receptors in URD IICT and broaden the success of alternative donor transplant, the only potentially curative therapy for many patients with advanced cancer.