NK RECEPTOR FUNCTION IN HAEMATOPOIETIC STEM CELL TRANSPLANTATION

造血干细胞移植中的 NK 受体功能

• 批准号: 8245880
• 负责人: Bo Dupont
• 金额: $ 26.95万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245880
• 关键词: Address; Affect; Alloantigen; Allogenic; Allografting; Autologous; CD34 gene; CD94 Antigen; Cells; Codon Nucleotides; Competence; Data; Development; Donor Selection; Engraftment; Environment; Exhibits; Extracellular Domain; Family; Genes; Genotype; HLA-Bw4; Haplotypes; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Human; Immunobiology; In Vitro; Individual; Infusion procedures; KIR3DS1; Ligands; MHC antigen; Marrow; Mediating; Methods; NK Cell Activation; NK cell receptor NKB1; Natural Killer Cells; Patients; Pattern; Phenotype; Resistance; Self Tolerance; Somatic Cell; Source; Specificity; T-Lymphocyte; Testing; Time; Transplantation; Umbilical Cord Blood; anergy; functional gain; in vivo Model; killer immunoglobulin-like receptor; leukemia; receptor; response

The overall objectives for the studies proposed in this project is to delineate the mechanisms by which human Natural Killer cells are tolerant to normal autologous somatic cells; and define the conditions leading to NK cell activation by allogeneic cells. It has been proposed that NK cells in normal individuals achieve self-tolerance by endowing functional competence only to the inhibitory Killer immunoglobulin-like Receptors (KIR) for which they exhibit cognate HLA ligands. We hypothesize that engrafting NK cells following allogeneic hematopoietic stem cell transplantation (HCT) acquire tolerance to self through selective anergy of non-self inhibitory KIR. Prior to this acquisition of tolerance, donor NK alloreactivity due to missing KIR ligand in the host may be most evident. We also hypothesize that recognition of HLA class I by activating KIR only occurs when the HLA molecule is presented as an alloantigen,Jn contrast, when the HLA molecule is a self HLA molecule, the activating KIR is tolerized or unresponsive. These hypotheses will be tested in four specific aims: #1: Determine how NK alloreactivity is influenced by presence of activating KIRs KIR2DS2, 2DS1 and 3DS1 in individuals with different combinations of KIRhaplotypes andHLAclass I genotypes. This will beachieved bydetermining (a) if presence of the activating KIRs 2DS1, 2DS2 or 3DS1 correlates with a NK cell mediated alloresponse with specificity for the HLA-Cw and HLA-Bw4 KIR-ligand groups and (b) determine the functional NK phenotype in donors with the genes for the activating KIRs 2DS1, 2DS2 or 3DS1 and the corresponding KIR-HLA ligand group as self MHC antigen. #2: Determine if the development of NK cell alloreactivity and self tolerance associated with activating KIRs develops gradually over time during the period of engraftment. We will also examine if engrafting NK cells at any time display alloreactivity that deviates from donor NK alloreactivity. #3: (a) Determine acquisition of NK tolerance to self during'engraftment. We will determine if an initial period of hyper-responsiveness of inhibitory KIR is followed by selective anergy of non-self MHC-specific KIR. (b) Determine if the presence of T-cells in the allograft affects inhibitory KIR-mediated NK response. #4: Determine the acquisition of NK receptors to HLA class I during NK development in vitro. Wewill investigate NK development ex vivo from CD34 cells obtained from Cord Blood and other sources. We will determine the sequential acquisition of NK receptors, and differential acquisition of receptors within the same receptor family; determine their acquisition of function, tolerance to self and allogeneic reactivity. We will determine if these developmental patterns are affected by the HLA class I phenotype expressed in the stromal culture environment. Relevance: These studies will facilitate development of new methods for donor selection for patients with leukemia and for treatment with NK cell infusions post transplantation to enhance engraftment and leukemia resistance.

该项目提出的研究的总体目标是描述人类的机制 天然杀伤细胞耐受性自体体细胞。并定义导致NK单元的条件 同种异细胞激活。已经提出，正常个体中的NK细胞通过 仅赋予抑制性杀伤性免疫球蛋白样受体（KIR）的功能能力 展示同源HLA配体。我们假设在同种异体造血茎上雕刻NK细胞 细胞移植（HCT）通过选择性抑制性KIR获得对自我的耐受性。之前 由于宿主中缺少KIR配体而导致的供体NK同种反应性可能是最明显的。 我们还假设仅在HLA分子为 当HLA分子是一个自hla分子时，以同种抗原的对比表示，激活的kir为 耐受性或反应迟钝。这些假设将以四个特定目的进行测试：＃1：确定NK的方式 同种反应性受激活Kir2dds2、2DDS1和3DS1的存在的影响 Kirhaplotypes Andhlaclass I基因型的组合。如果存在 激活KIRS 2DS1、2DDS2或3DDS1的激活中，与NK细胞介导的同种异体响应与特异性相关 HLA-CW和HLA-BW4 KIR-配体组以及（b）确定供体的功能性NK表型 激活KIRS 2DS1、2DDS2或3DS1的基因和相应的Kir-HLA配体作为自MHC 抗原。 ＃2：确定NK细胞的发展是否与激活相关 在植入期间，KIRS随着时间的流逝而逐渐发展。我们还将检查是否植入NK单元 在任何时候，都会显示出偏离捐助者NK同种异体反应性的同种异体反应性。 ＃3：（a）确定获得NK的获取 在移植期间对自我的容忍。我们将确定抑制性的初始响应性是否 KIR之后是非自我MHC特异性KIR的选择性反感。 （b）确定是否存在T细胞 同种异体移植会影响抑制性KIR介导的NK反应。 ＃4：确定对HLA的NK受体的获取 NK开发期间的I类体外。我们将研究从获得的CD34细胞的NK发育ex Vivo 来自脐带血和其他来源。我们将确定NK受体的顺序采集，以及 同一受体家族中受体的差异获取；确定其功能的获取， 对自我和同种异反应性的耐受性。我们将确定这些发展模式是否受到 HLA I类表型在基质培养环境中表达。相关性：这些研究将有助于 开发为白血病患者和NK细胞治疗的新方法开发供体选择方法 移植后输注以增强植入和白血病耐药性。