Understanding the impact of human NKT cells on hematopoiesis

了解人类 NKT 细胞对造血的影响

• 批准号: 9096694
• 负责人: Jenny E. Gumperz
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096694
• 关键词: Affect; Anabolism; Antigens; Apyrase; Binding; Biological Assay; Biological Models; Blocking Antibodies; Bone Marrow; CD1d antigen; CD34 gene; CSF2 gene; CSF3 gene; Cell Communication; Cell physiology; Cells; Clinical; Code; Color; Communicable Diseases; Correlative Study; Cytokine Receptors; Data; Development; Dietary Fats; Dinoprostone; Disease; Engraftment; Environment; Enzymes; Event; Exposure to; Figs - dietary; Frequencies; Future; Glycolipids; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Granulopoiesis; HIV; Health; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune; Immunotherapy; In Vitro; Incidence; Inflammatory; Investigation; Lead; Link; Lipids; Lymphocyte; Malignant Neoplasms; Mediating; Molecular; Mus; Myelogenous; Myelopoiesis; Outcome; Pathway interactions; Patients; Play; Population; Principal Investigator; Procedures; Process; Production; Prostaglandin Antagonists; Prostaglandin E Receptor; Publishing; Recovery; Recurrent disease; Research; Role; Severities; Signal Pathway; Signal Transduction; Stem cells; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Work; cell type; clinically relevant; cytokine; design; extracellular; graft vs host disease; hematopoietic stem cell fate; high risk; improved; in vivo; in vivo Model; inhibitor/antagonist; killer T cell; lipid mediator; migration; monocyte; mouse model; neutrophil; programs; radioresistant; reconstitution; research study; self-renewal; stem cell differentiation

 DESCRIPTION (provided by applicant): Transplantation of human umbilical cord blood hematopoietic stem cells (HSCs) has become a standard procedure to treat high-risk hematologic malignancies as well as other hematological disorders, and also holds promise as a therapy for certain infectious diseases (e.g. HIV). However, hematopoietic engraftment following cord blood transplantation in clinical settings is frequently suboptimal due to low numbers of transferred CD34+ stem cells, and slow reconstitution of neutrophils is often associated with post-transplant complications. Prior work in murine models and correlative studies of human patients have established that invariant Natural Killer T (iNKT) cells play important roles in promoting both HSC engraftment and myelopoiesis after transplantation, yet the mechanisms by which they mediate these effects remain poorly understood. Preliminary studies have demonstrated that iNKT cells produce cytokines such as GM-CSF, trigger CD40 signaling, and activate purinergic signaling and PGE2 production by other cells - all of which are activities that have been implicated in promoting key hematopoietic events such as HSC self-renewal, migration, and myeloid differentiation. The overarching goal of the studies proposed here is to understand the cellular interactions and molecular signaling pathways engaged by iNKT cells during post-transplant hematopoiesis, and to associate these with particular hematopoietic outcomes. We will use complementary in vitro and in vivo model systems to dissect iNKT- mediated mechanistic processes and to test the effects of human iNKT cells on the engraftment and differentiation of human cord blood HSCs after transplantation into highly immune deficient NSG mice. Since iNKT cells might interact with multiple different cell types and engage multiple different molecular pathways to influence hematopoietic outcomes, Aim 1 will determine the impact of direct iNKT-HSC interactions as compared to the indirect effects of soluble hematopoietic factors produced during iNKT interactions with other cell types, and Aim 2 will determine the impact of specific signaling pathways engaged by iNKT cells that could be utilized in either direct or indirect pathways. These studies will advance the field by distinguishing how iNKT-mediated pathways contribute to different outcomes following HSC transplantation, which will further our ability to design therapeutic strategies that engage these unique innate T lymphocytes. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

 描述（由申请人提供）：人类脐带血造血干细胞（HSC）移植已成为治疗高危血液恶性肿瘤以及其他血液疾病的标准程序，并且也有望作为某些传染病（例如艾滋病毒）的治疗方法。然而，在临床环境中，由于移植的 CD34+ 干细胞数量较少，脐带血移植后的造血植入常常不是最理想的，并且中性粒细胞的缓慢重建通常与移植后并发症有关。先前对小鼠模型的研究和对人类患者的相关研究已经证实，不变的自然杀伤 T (iNKT) 细胞在促进移植后 HSC 植入和骨髓生成方面发挥着重要作用，但它们介导这些作用的机制仍知之甚少。初步研究表明，iNKT 细胞产生 GM-CSF 等细胞因子，触发 CD40 信号传导，并激活其他细胞的嘌呤能信号传导和 PGE2 产生，所有这些活动都与促进 HSC 自我更新、迁移和骨髓分化等关键造血事件有关。这里提出的研究的总体目标是了解移植后造血过程中 iNKT 细胞参与的细胞相互作用和分子信号传导途径，并将这些与特定的造血结果联系起来。我们将使用互补的体外和体内模型系统来剖析 iNKT 介导的机制过程，并测试人类 iNKT 细胞移植到高度免疫缺陷的 NSG 小鼠后对人脐带血 HSC 的植入和分化的影响。由于 iNKT 细胞可能与多种不同的细胞类型相互作用，并参与多种不同的分子途径来影响造血结果，目标 1 将确定直接 iNKT-HSC 相互作用的影响，与 iNKT 与其他细胞类型相互作用期间产生的可溶性造血因子的间接影响进行比较，目标 2 将确定 iNKT 细胞参与的特定信号传导途径的影响，这些信号传导途径可用于直接或间接途径。这些研究将通过区分 iNKT 介导的途径如何促进 HSC 移植后的不同结果来推进该领域的发展，这将进一步提高我们设计利用这些独特的先天 T 淋巴细胞的治疗策略的能力。 PHS 398/2590（修订版 06/09） 页面延续 格式页面