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：人类树突状细胞与同种异体移植中先天性和适应性免疫的发生 造血移植 该新项目将坚持本P01关于同种异体移植后早期事件的主题重点 促进免疫重建和维持自由造血干细胞移植（alloHSCT 从复发。针对次要组织相容性抗原（miHA）的T细胞应答和自然免疫的发生 杀伤（NK）细胞库与移植后早期发生的这些过程密切相关。到 为了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，而不是传出或效应臂，并确定不同的作用 由人类树突状细胞（DC）的定义亚型发挥作用。然后将在临床前小鼠中进行测试 模型我们的目的是最终将基于免疫的干预靶向一种或另一种DC亚型， 为了将移植物抗宿主病（GvHD）的并发症与移植物抗宿主病的期望益处分离， 肿瘤/白血病/淋巴瘤（GvT/GvL）以及先天免疫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）检测CD 34+衍生的 Langerhans型树突状细胞（LC）刺激更强大的T细胞应答， 组织相容性抗原（miHA）比其他两种类型的常规或骨髓DC;（2）确定 哪一种人DC类型在形成NK细胞抑制性KIR库和免疫应答方面最有效。 其发生的机制;和（3）使用小鼠移植模型来评估相对效力 骨髓来源的DC（人单核细胞来源的DC对应物）与LC和真皮间质DC的比较 （DDC-IDC）在GvH和GvT/GvL应答中的作用。更好地理解细胞机制 这些过程的基础，特别是特定DC亚型的贡献，应该阐明 控制点，以操纵alloHSCT后的免疫结果。 通俗总结和公共卫生相关性：专门的白色血细胞，称为树突状细胞，是至关重要的 对白血病、淋巴瘤和其他肿瘤移植患者的免疫力。了解 树突状细胞在移植过程中的功能应该有助于医生更好地控制肿瘤的发展， 免疫系统这应该有利于预防疾病复发和重建有益的免疫力，