NK Receptor Function in Hematopoietic Stem Cell Transplantation

P r o j e c t 1 异基因造血干细胞移植(Hct)是治疗某些疾病的唯一选择。 恶性血液病，包括急性髓系白血病(AML)，尽管 HI_A基因的干细胞捐赠者和接受者，超过一半的患者的结果仍然令人失望 由于移植后的并发症，如白血病复发和病毒重新激活。捐赠人的激活 自然杀伤(NK)细胞是先天免疫系统的关键组成部分，可以显著防止这些 减少并发症，改善血细胞移植结局。NK反应由NK KIR和NK KIR之间的相互作用决定 受体及其人类白细胞抗原配体。确定哪些KIR/HLA相互作用对NK功能影响最大 了解这些相互作用是如何发生的，对于选择捐赠者的最终目标至关重要 以KIR和人类白细胞抗原为基础，有利于NK活化，改善血细胞移植结局。该提案的第一个目的是使用 一种独特的转基因小鼠系统和FRET技术证明抑制性KIR分子 与相邻细胞(反式)和NK细胞本身(顺式)呈现的人类白细胞抗原的相互作用都可以形成 NK功能。这些结果与预测人类白细胞抗原相合和不相合的NK反应有直接关系 HCT。第二个目的是证明激活的KIR2DS1和KIR3DS1在依赖于人类白细胞抗原的 解释具有KIR配体的患者的KIR2DS1的发现 HL A-C1与HCT后较低的复发率有关，KIR3DS1与较低的CMV有关 重新激活。ALM 1和ALM 2的研究结果将支持这样的概念，即要捕获Hct中的NK激活， 必须将NK抑制降至最低。一种基于KIR/人类白细胞抗原基因分型最大化的供者选择算法 NK活性和改善红细胞压积的结果被提出。第三个目标是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 该算法的可行性和临床影响的展示将潜在地改变捐赠者的选择 基于HIA的策略到基于KIR/HLA的策略，该策略将利用先天免疫效应来对抗 感染和复发不会增加T细胞同种异体反应和移植物抗宿主病的风险。 相关性(请参阅说明)： 自然杀伤(NK)细胞是人体免疫系统的重要组成部分，保护个人免受 病毒感染和罹患癌症。这项提议旨在帮助骨髓移植。 医生了解是什么控制了NK细胞，这样他们就可以利用NK细胞和免疫系统来对抗病毒 感染和白血病。 项目/绩效网站(S)(如果需要额外空间，请使用项目/绩效网站格式页面) 项目/

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/