Elucidation of Human Natural Killer Cell Development

人类自然杀伤细胞发育的阐明

• 批准号: 10091309
• 负责人: AHARON G FREUD
• 金额: $ 35.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091309
• 关键词: Acquired Immunodeficiency Syndrome; Acute Myelocytic Leukemia; Acute leukemia; Address; Allogenic; Biological Assay; Bone Marrow; CD34 gene; Cause of Death; Cell Differentiation process; Cell Maturation; Cell Separation; Cell physiology; Cessation of life; Chemoresistance; Child; Clinical; Clinical Data; Coculture Techniques; Complement; Conflict (Psychology); Coupled; Cytomegalovirus; Data; Dendritic Cells; Development; Disease remission; Effector Cell; Flow Cytometry; Gene Expression Profile; Goals; Helper-Inducer T-Lymphocyte; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility; Homologous Transplantation; Human; Human papilloma virus infection; Immune Targeting; Immune system; Immunity; Immunocompetent; Immunologic Surveillance; Immunology; Immunotherapy; In Situ; In Vitro; KLRD1 gene; Knowledge; Light; Link; Location; Lymphoid Cell; Lymphoid Tissue; Lymphoma; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical; Methods; Mission; Molecular; Mus; Natural Killer Cells; Outcome; Parents; Pathway interactions; Patients; Phenotype; Play; Population; Procedures; Process; Publishing; Receptor Activation; Receptor Cell; Recurrent disease; Regulation; Research; Risk; Role; Science; Scientist; Secondary to; Seminal; Series; Siblings; Signal Transduction; Surface; Survival Rate; System; T-Lymphocyte; Testing; Tissues; Transplantation; United States; Work; cancer cell; cancer immunotherapy; cell type; chemotherapy; clinically relevant; comorbidity; cytotoxic; design; experimental study; graft vs host disease; graft vs leukemia effect; immune activation; immune checkpoint; immune function; improved; improved outcome; in vivo; killer immunoglobulin-like receptor; laser capture microdissection; malignant breast neoplasm; new therapeutic target; novel; older patient; p80 natural killer cell receptor; post-transplant; prevent; receptor; receptor binding; stem cells; success; vaccine development

This proposal focuses on elucidation of the processes regulating human natural killer (NK) cell development. Our specific aims are: 1) To define the microenvironment(s) and characterize the regulation of NK cell differentiation in human secondary lymphoid tissues (SLT); and 2) To define the order, regulation, and phenotypic impact of major histocompatibility complex molecule binding receptor (MBR) acquisition during human NK cell maturation. NK cells are innate lymphoid cells (ILC) that have direct cytotoxic function against cancer cells. NK cells play a vital role in immune surveillance against malignant transformation by complementing T cell immunity, and they can mediate an important graft-versus-leukemia effect in the setting of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). Our overall goal in this proposal is to gain a comprehensive understanding of the cellular and molecular components that regulate human NK cell development and function in order to best understand how they work and can be enhanced in the face of malignancy. In particular, in Aim 1 we will define the cellular microenvironment(s) within SLT in which human NK cell developmental intermediates (NKDI) reside and differentiate. We previously identified and characterized the full spectrum of NKDI in these tissues. Over the past five years, additional and closely-related ILC subsets have been discovered and characterized, and we have preliminary data to indicate that all ILCs derive from a common ILC progenitor population that is naturally restricted to SLT. We hypothesize that the cellular milieu within SLT influences NK cell differentiation from the common ILC progenitor, and we propose a series of experiments to test our hypothesis and also to elucidate the mechanism(s) by which SLT-derived “helper” cell populations influence this pathway. The goal of these studies is to identify new therapeutic targets to boost immune function in the post-transplant setting for AML. In Aim 2 we have preliminary data that suggest that NK cell functional maturation occurs in a stepwise fashion associated with the orderly and coordinated acquisition of the activation receptor, NKp80, and two types of MBRs: CD94/NKG2A and killer immunoglobulin-like receptors (KIR). What is not yet known and will be tested in our proposed experiments is how this orderly acquisition of receptors is regulated and in turn how signaling through the receptors themselves influences NK cell functional maturation. The clinical importance of these studies lies in the fact that each of these surface NK cell receptors has the potential to be targeted for immune checkpoint regulation in order to enhance NK cell-mediated immune therapy against cancer.

该提案的重点是阐明治理人类自然杀手（NK）细胞发育的过程。 我们的具体目的是：1）定义微环境并表征了NK细胞的调节 人类次要淋巴组织（SLT）的分化； 2）定义命令，法规和 主要组织相容性复合物分子结合受体（MBR）在期间的表型影响 人NK细胞成熟。 NK细胞是对癌细胞具有直接细胞毒性功能的先天淋巴样细胞（ILC）。 NK细胞播放 通过完成T细胞免疫来抵抗恶性转化的免疫监测中的重要作用，它们 在同种异体造血干细胞的情况下，可以介导重要的移植物与白血病效应 急性髓样白血病（AML）的移植。我们在此提案中的总体目标是获得全面的 了解调节人NK细胞发育的细胞和分子成分 功能以最好地了解它们的工作原理，并在面对恶性肿瘤时可以增强。 特别是，在AIM 1中，我们将定义SLT中的细胞微环境，其中人类NK细胞 发展中间体（NKDI）居住在区分。我们以前确定并表征了 这些组织中的NKDI全谱。在过去的五年中，额外且密切相关的ILC子集 已经发现和表征了 自然限于SLT的常见ILC祖先种群。我们假设细胞环境 在SLT中影响NK细胞与常见ILC祖细胞的分化，我们提出了一系列 测试我们的假设的实验，并阐明SLT衍生的“助手”细胞的机制 人口影响这一途径。这些研究的目的是确定新的治疗靶点以提高 AML移植后设置中的免疫功能。 在AIM 2中，我们有初步数据，表明NK细胞功能成熟发生在逐步中 与激活受体NKP80的有序和协调的收购相关的时尚 MBR的类型：CD94/NKG2A和杀手型免疫球蛋白样受体（KIR）。尚不清楚的 在我们提出的实验中进行测试是如何调节接收者的有序获取 通过接收器的信号本身会影响NK细胞功能成熟。临床重要性 这些研究在于这样一个事实，即这些表面NK细胞受体中的每一个都有可能针对的 免疫检查点调节以增强NK细胞介导的对癌症的免疫治疗。