NK Receptor Function in Hematopoietic Stem Cell Transplantation

NK受体在造血干细胞移植中的功能

• 批准号: 8435557
• 负责人: KATHARINE C HSU
• 金额: $ 30.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435557
• 关键词: Activities of Daily Living; Acute Myelocytic Leukemia; Algorithms; Allogenic; Allografting; Attenuated; Biology; Blood; Bone Marrow Transplantation; Cells; Clinical; Cytomegalovirus; Donor Selection; Environment; Fluorescence Resonance Energy Transfer; Genes; Genetic; Genotype; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune system; Individual; Infection; Instruction; KIR3DS1; Ligands; Malignant Neoplasms; Marrow; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Mus; Natural Killer Cells; Outcome; Patients; Physicians; Reagent; Recurrent disease; Relapse; Relative (related person); Risk; Shapes; Site; Stem cells; System; T-Lymphocyte; Technology; Transgenic Mice; Transplantation; Viral; Virus Diseases; Work; base; design; fighting; graft vs host disease; improved; in vivo; leukemia; mortality; novel; prevent; receptor; receptor function; response; viral leukemia

P r o j e c t 1 Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative option for patients with certain hematologic malignancies, including acute myelogenous leukemia (AML), Despite precise matching between stem cell donor and recipient for HI_A genes, outcomes for more than half of patients remain disappointing due to post-transplant complications, such as leukemic relapse and viral reactivation. Activation of donor natural killer (NK) cells, key components ofthe innate immune system, can significantly prevent these complications and Improve HCT outcomes. NK response is dictated by interactions between the NK KIR receptors and their HLA ligands. Determining which KIR/HLA interactions most potently impact NK function and understanding how these Interactions take place is vital to the ultimate objective of selecting donors based on KIR and HLA to favor NK activation and improve HCT outcomes. The first aim ofthe proposal uses a unique transgenic mouse system and FRET technology to demonstrate that inhibitory KIR molecules interacting with HLA presented by adjacent cells (trans) as well as by the NK cell itself (cis) can both shape NK function. These results are directly relevant to predicting NK response in HLA-matched and mismatched HCT. The second aim is to show that the activating KIR2DS1 and KIR3DS1 contribute in an HLA-dependent manner to the functional capacity of the cell, explaining findings that KIR2DS1 in patients with the KIR ligand HLA-C1 is associated with lower relapse following HCT and that KIR3DS1 is associated with lower CMV reactivation. Findings from Alms 1 and 2 will support the concept that to capture NK activation In HCT, one must minimize NK inhibition. A novel donor selection algorithm based on KIR/HLA genotypes to maximize NK activity and improve HCT outcomes Is presented. The third aim seeks to apply this algorithm to donor selection, comparing outcomes post-selection with historic outcomes of HCT patients. Successful demonstration ofthe algorithm's feasibility and clinical impact will potentially change donor selection from an HIA-based strategy to a KIR/HLA-based strategy that will take advantage of innate immune effects against infection and relapse without increasing the risk of T-cell alloreactivity and graft-versus-host disease. RELEVANCE (See instructions): Natural killer (NK) cells are a vital component ofthe body's immune system, protecting the individual from viral infections and from developing cancer. This proposal is designed to help bone marrow transplant doctors understand what controls NK cells so that they can use NK cells and the immune system to fight viral infections and leukemia. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Proiect/Perfonnance Site Fomiat Page) Project/

项目1 异基因造血干细胞移植（HCT）是某些患有某些疾病的患者唯一的治疗选择 血液系统恶性肿瘤，包括急性髓性白血病 (AML)，尽管两者之间存在精确匹配 HI_A 基因的干细胞供体和受体，超过一半患者的结果仍然令人失望 由于移植后并发症，例如白血病复发和病毒再激活。激活捐赠者 自然杀伤 (NK) 细胞是先天免疫系统的关键组成部分，可以显着预防这些疾病 并发症并改善 HCT 结果。 NK 反应由 NK KIR 之间的相互作用决定 受体及其 HLA 配体。确定哪些 KIR/HLA 相互作用最能影响 NK 功能 了解这些相互作用如何发生对于选择捐助者的最终目标至关重要 基于 KIR 和 HLA，有利于 NK 激活并改善 HCT 结果。该提案的第一个目标是使用 独特的转基因小鼠系统和 FRET 技术证明抑制性 KIR 分子 与邻近细胞（反式）以及 NK 细胞本身（顺式）呈递的 HLA 相互作用都可以塑造 NK 功能。这些结果与预测 HLA 匹配和不匹配的 NK 反应直接相关 血细胞CT。第二个目的是证明激活 KIR2DS1 和 KIR3DS1 有助于 HLA 依赖性 细胞功能能力的方式，解释了 KIR2DS1 在具有 KIR 配体的患者中的发现 HLA-C1 与 HCT 后较低的复发率相关，KIR3DS1 与较低的 CMV 相关 重新激活。施舍 1 和 2 的发现将支持这一概念，即在 HCT 中捕获 NK 激活，一个 必须尽量减少 NK 抑制。一种基于 KIR/HLA 基因型的新型供体选择算法，以最大化 介绍了 NK 活性和改善 HCT 结果。第三个目标旨在将该算法应用于捐赠者 选择，将选择后的结果与 HCT 患者的历史结果进行比较。成功的 该算法的可行性和临床影响的证明将有可能改变捐赠者的选择 基于 HIA 的策略转变为基于 KIR/HLA 的策略，该策略将利用先天免疫效应来对抗 感染和复发，而不增加 T 细胞同种异体反应性和移植物抗宿主病的风险。 相关性（参见说明）： 自然杀伤 (NK) 细胞是人体免疫系统的重要组成部分，可保护个体免受 病毒感染和癌症。该提案旨在帮助骨髓移植 医生了解 NK 细胞的控制因素，以便他们能够利用 NK 细胞和免疫系统来对抗病毒 感染和白血病。 项目/性能站点（如果需要额外空间，请使用项目/性能站点格式页面） 项目/