NK cells, their receptors and unrelated donor transplant

NK 细胞、其受体和无关的供体移植

• 批准号: 8533745
• 负责人: Jeffrey S. Miller
• 金额: $ 181.58万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-17 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8533745
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Adoptive Transfer; Affect; Allogenic; Autologous; B-Lymphocytes; Back; Binding; Biological; Biological Assay; Biology; Biometry; Blood; CD34 gene; CD94 Antigen; Cell Line; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Cellular biology; Characteristics; Child; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Conduct Clinical Trials; Cytomegalovirus; DNA; Data; Data Quality; Development; Disease; Disease-Free Survival; Doctor of Philosophy; Donor Selection; Donor person; Dose; Education; Exhibits; Exposure to; Foundations; Funding; Future; Gene Cluster; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genotype; Goals; HLA-C Antigens; Haplotypes; Health; Hematopoietic Neoplasms; Hematopoietic stem cells; Homologous Transplantation; Human; Immunogenetics; Immunotherapy; In Vitro; In complete remission; Individual; Informatics; Infusion procedures; Interleukin-15; International; Investigation; Knowledge; Laboratories; Lead; Length; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Methods; Minnesota; Molecular; Multicenter Trials; Myeloid Leukemia; Natural Killer Cells; Organ Transplantation; Outcome; Patients; Phase I Clinical Trials; Play; Population; Pregnancy; Program Research Project Grants; Protocols documentation; Quality of life; Receptor Gene; Refractory; Regimen; Regulation; Relapse; Research; Research Support; Resistance; Resolution; Resources; Risk; Role; Safety; Sampling; Science; Series; Shapes; Solid; Solid Neoplasm; Specificity; Stem cells; T-Lymphocyte; Testing; Therapeutic; Translating; Translations; Transplant Recipients; Transplantation; Tumor Burden; Universities; Variant; Virus Diseases; Work; base; bench to bedside; clinical application; clinical effect; cohort; conditioning; cytokine; cytotoxicity; design; genetic analysis; hematopoietic cell transplantation; improved; in vivo; killer inhibitory receptor; killings; leukemia; novel; programs; promoter; protective effect; receptor; receptor expression; receptor function; reconstitution; repository; research study; response; success

Transplant donors have either the B/x or A/A KIR genotype. During the current period of support we found that unrelated donors having B/x genotype confer significant relapse-free survival benefit to transplanted AML patients. By refining the analysis to separate B haplotype components, we defined a 'B-content score' as the best predictor of superior clinical outcomes. We propose that donor selection based on KIR, as well as HLA, genotyping should become standard practice for therapeutic transplants for AML. This Program will test the hypotheses that NK cells are of general importance in allogeneic transplantation and that variable NK cell receptor interactions influence clinical outcome. Conducting this Program is an international group of experts in NK cell biology and clinical transplantation. A focus for study is the thousands of transplants performed through the auspices of the NMDP, their associated blood and DNA samples, and the extensive high quality data on transplant outcome available through the CIBMTR. Project 1 (Peter Parham) will focus on the functions of characteristic B haplotype KIR, to determine the mechanisms by which they can influence transplant outcome. In Project 2, Jeffrey Miller proposes to evaluate NK cell education after adoptive transfer of haploidentical stem cells and subsequent reconstitution. He proposes a first human trial to investigate the capacity of hulL-15 to educate NK cells in vivo. In Project 3, Daniel Weisdorf will develop KIR typing for clinical use in selecting donors with KIR that improve transplant outcome. This method will also be used in the human trial of Project 2. Synergistic interaction between the Projects will take basic NK cell science from bench to bedside. Achieving this goal through better donor selection, understanding of NK cell regulation by KIR genetics and how best to exploit this knowledge clinically. As well as Administration and Clinical Research Support (Core A) and Biostatistics (Core B), the research will be supported by unique Informatics (Core C) and KIR genotyping (Core D) resources. This program will establish definitive roles for NK cells and their receptors in allogeneic transplantation and adoptive NK cell transfer. The program also promises to change practice of allogeneic transplantation, to the greater benefit of patients with advanced leukemia.

移植供体具有 B/x 或 A/A KIR 基因型。在当前的支持期间，我们发现具有 B/x 基因型的无关捐赠者可为移植的 AML 患者带来显着的无复发生存益处。通过细化分析以分离 B 单倍型成分，我们将“B 含量评分”定义为优异临床结果的最佳预测指标。我们建议基于 KIR 以及 HLA 和基因分型的供体选择应成为 AML 治疗性移植的标准做法。该计划将测试以下假设：NK 细胞在同种异体移植中具有普遍重要性，并且不同的 NK 细胞受体相互作用会影响临床结果。执行该计划的是一个由 NK 细胞生物学和临床移植领域的专家组成的国际小组。研究的重点是在 NMDP 的支持下进行的数千例移植手术、相关的血液和 DNA 样本，以及通过 CIBMTR 获得的关于移植结果的广泛高质量数据。项目 1 (Peter Parham) 将重点关注特征 B 单倍型 KIR 的功能，以确定它们影响移植结果的机制。在项目 2 中，Jeffrey Miller 建议在单倍体干细胞过继转移和随后的重建后评估 NK 细胞的培养。他提议进行首次人体试验，以研究 hulL-15 在体内培养 NK 细胞的能力。在项目 3 中，Daniel Weisdorf 将开发 KIR 分型，用于临床选择具有 KIR 的捐赠者，从而改善移植结果。该方法也将用于项目 2 的人体试验。项目之间的协同相互作用将使基础 NK 细胞科学从实验室走向临床。通过更好地选择供体、了解 KIR 遗传学对 NK 细胞的调节以及如何在临床上最好地利用这些知识来实现​​这一目标。除了管理和临床研究支持（核心 A）和生物统计学（核心 B）外，该研究还将得到独特的信息学（核心 C）和 KIR 基因分型（核心 D）资源的支持。该计划将确定 NK 细胞及其受体在同种异体移植和过继 NK 细胞转移中的明确作用。该计划还承诺改变同种异体移植的做法，为晚期白血病患者带来更大的利益。