HUMAN DENDRITIC CELLS AND THE ONSET OF INNATE AND ADAPTIVE IMMUNITY IN ALLOGENEIC

人类树突细胞和同种异体中先天性和适应性免疫的发生

• 批准号: 7318390
• 负责人: James William Young
• 金额: $ 29.02万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318390
• 关键词: Allogenic; Antigen Presentation; Autologous; Blood; Bone Marrow; Cells; Cross Presentation; Dendritic Cells; Dermal; Development; Event; Freedom; H-Y Antigen; HLA-B Antigens; Hematopoietic; Hematopoietic Stem Cell Transplantation; Histocompatibility; Human; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunologics; Individual; Intention; Interleukin-15; Interleukin-18; Intervention; Langerhans cell; Leukocytes; Licensing; Ligands; Minor; Modeling; Mus; Myelogenous; Natural Killer Cells; Outcome; Pathway interactions; Process; Public Health; Relapse; Relative (related person); Role playing therapy; Shapes; Sorting - Cell Movement; T-Lymphocyte; Testing; Transplant Recipients; Transplantation; Upper arm; Zalcitabine; base; cell type; cytotoxicity; desire; disorder later incidence prevention; graft vs host disease; improved; interstitial; leukemia; leukemia/lymphoma; monocyte; mouse model; pre-clinical; receptor; reconstitution; research study; response; sex; tumor

PROJECT 3: Human dendritic cells and the onset of innate andadaptive immunity in allogeneic hematopoietic transplantation This new project will adhere to the thematic emphasis of this P01 on the early events after allogeneic hematopoietic stem cell transplantation (alloHSCT) that promote immune reconstitution and sustain freedom from relapse. T cell responses against minor histocompatibility Ags (miHA) and development of the natural killer (NK) cell repertoire are critically intertwined with these processes occurring early post-transplant. To improve our understanding of the biologic mechanisms underlying these immune responses, we will focus on the afferent, rather than efferent or effector arm of the immune response, and identify the distinct roles played by defined subtypes of human dendritic cells (DCs). These will then be tested in a preclinical mouse model. Our intention is eventually to target immune-based interventions to one or another DC subtype, in order to isolate the complications of graft-vs-host disease (GvHD), from the desired benefits of graft-vs- tumor/leukemia/lymphoma (GvT/GvL) and successful reconstitution of innate and adaptive immunity, at the level of antigen presentation. We will therefore approach these issues by (1) testing whether CD34+-derived Langerhans-type dendritic cells (LCs) stimulate more robust T cell responses against minor histocompatibility Ags (miHA) than do the other two types of conventional or myeloid DCs; (2) determining which human DC type is most effective in shaping the NK cell inhibitory KIR repertoire and the immunologic mechanism(s) by which this occurs; and (3) using mouse transplant models to evaluate the relative potency of bone marrow derived DCs (human monocyte-derived DC counterparts) vs LCs and dermal-interstitial DCs (DDC-IDCs) in GvH and GvT/GvL responses. An improved understanding of the cellular mechanisms underlying these processes, and in particular the contribution of specific DC subtypes, should elucidate control points to manipulate immunologic outcomes after alloHSCT. Lay summary and public health relevance: Specialized white blood cells, called dendritic cells, are critical to the immunity of patients transplanted for leukemia, lymphoma, and other tumors. Understanding the function of dendritic cells in the context of transplantation should help doctors better control the developing immune system. This should favor prevention of disease recurrence and redevelopment of helpful immunity,

项目 3：人类树突状细胞和同种异体中先天性和适应性免疫的开始 造血移植 这个新项目将秉承本 P01 的主题重点，即异体移植后的早期事件 促进免疫重建和维持自由的造血干细胞移植（alloHSCT） 免于复发。 T 细胞针对次要组织相容性抗原 (miHA) 的反应以及天然抗原的发育 杀伤（NK）细胞库与移植后早期发生的这些过程密切相关。到 提高我们对这些免疫反应背后的生物学机制的理解，我们将重点关注 免疫反应的传入臂，而不是传出臂或效应臂，并确定不同的作用 由人类树突状细胞 (DC) 的特定亚型发挥作用。然后将在临床前小鼠中进行测试 模型。我们的目的最终是针对一种或另一种 DC 亚型进行基于免疫的干预措施， 为了将移植物抗宿主病（GvHD）的并发症与移植物抗宿主病的预期益处分开 肿瘤/白血病/淋巴瘤（GvT/GvL）以及先天性和适应性免疫的成功重建 抗原呈递水平。因此，我们将通过 (1) 测试 CD34+ 是否衍生来解决这些问题 朗格汉斯型树突状细胞 (LC) 可刺激更强大的 T 细胞针对轻微症状的反应 组织相容性 Ag (miHA) 优于其他两种类型的常规或骨髓 DC； (2)确定 哪种人类 DC 类型在塑造 NK 细胞抑制 KIR 库和免疫学方面最有效 发生这种情况的机制； (3) 使用小鼠移植模型评估相对效力 骨髓衍生的 DC（人单核细胞衍生的 DC 对应物）与 LC 和真皮间质 DC 的比较 (DDC-IDC) 在 GvH 和 GvT/GvL 响应中。加深对细胞机制的理解 应阐明这些过程的基础，特别是特定 DC 亚型的贡献 alloHSCT 后控制免疫结果的控制点。 简单总结和公共卫生相关性：称为树突状细胞的特殊白细胞至关重要 提高白血病、淋巴瘤和其他肿瘤移植患者的免疫力。了解 树突状细胞在移植中的功能应该有助于医生更好地控制发育 免疫系统。这应该有利于预防疾病复发和重建有用的免疫力，