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基因型的无关供体赋予移植AML患者的无重大复发生存益处。通过完善分析以分离B单倍型组件，我们将“ B-含量分数”定义为出色临床结果的最佳预测指标。我们建议基于KIR和HLA的供体选择，基因分型应成为AML治疗移植物的标准实践。该程序将测试NK细胞在同种异体移植中至关重要的假设，并且可变的NK细胞受体相互作用会影响临床结果。进行该计划是NK细胞生物学和临床移植方面的国际专家组。研究的重点是通过NMDP的主持，其相关的血液和DNA样本进行的数千种移植物，以及通过CIBMTR提供的有关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，以确定它们可以影响移植结果的机制。在项目2中，杰弗里·米勒（Jeffrey Miller）提议在收养单倍型干细胞和随后的重建后评估NK细胞教育。他提出了第一个人类试验，以调查船体15在体内教育NK细胞的能力。在项目3中，丹尼尔·韦斯多夫（Daniel Weisdorf）将开发KIR打字，以供临床使用，以选择KIR的供体，以改善移植结果。该方法还将用于项目2的人体试验中。项目之间的协同互动将使基本的N​​K细胞科学从长凳到床边。通过更好的供体选择，了解KIR遗传学调节NK细胞调节以及如何最好地在临床上利用这一知识来实现​​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。该程序将在同种异体移植和收养NK细胞转移中为NK细胞及其受体建立明确的作用。该计划还有望改变同种异体移植的实践，从而将晚期白血病患者的益处更大。