Dendritic Cell Subsets and Paths of Maturation in GVHD

GVHD 中的树突状细胞亚群和成熟途径

• 批准号: 7147377
• 负责人: Warren D Shlomchik
• 金额: $ 20.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147377
• 关键词: CD40 molecule; T lymphocyte; apoptosis; artificial immunosuppression; biological signal transduction; cell differentiation; cell population study; cytokine receptors; dendritic cells; genetically modified animals; graft versus host disease; histocompatibility; homologous transplantation; immunotoxicity; laboratory mouse; radiation immunosuppression; stem cell transplantation; toll like receptor; transplantation immunology; tumor necrosis factor alpha; urate

DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (alloSCT) is a life-saving therapy for hematologic malignancies and inherited disorders such as sickle cell anemia and thalassemia. T cells in alloSCT grafts play two pivotal roles: 1) they reconstitute T cell immunity in adults who, due to thymic involution, do not develop significant numbers of donor stem cell-derived T cells; and 2) they mediate an antineoplastic effect. Unfortunately, donor T cells also cause Graft-vs.-Host Disease (GVHD), the attack of donor T cells against recipient tissues. Therefore, all patients receive GVHD prophylaxis either via depletion of T cells from the allograft or with agents that impair T cell function. Nevertheless, GVHD and the infectious complications of immunosuppression are the major causes of morbidity in alloSCT. Professional antigen presenting cells (APCs) initiate alloimmune T cell responses by priming rare alloreactive T cells. Several features distinguish antigen presentation in transplantation from paradigms established in infectious models. First, alloSCT recipients are chimeric for donor and host APCs. Our work to date focused on characterizing the distinct roles for donor and host APCs in GVHD pathogenesis. Second, the roles of dendritic cell (DC) subsets, which in infectious models have distinct properties, have not been well defined in transplantation models. The development of effective strategies to target them to decrease GVHD depends on this knowledge. Third, the current model for DCs in adaptive immunity, in which pathogen-derived ligands for pattern associated molecular pattern receptors, stimulate immature DCs to mature and migrate to secondary lymph nodes, may not apply in alloSCT where there are no specific infectious pathogens, all recipient APCs present alloantigen and signals that induce DC maturation are unknown. In this proposal we: 1) use novel transgenic mice that lack DCs or DC subsets, antibodies and immunotoxins to define critical APC subsets in GVHD; and 2) use transgenic and and gene-deficient mice to test hypotheses regarding how DCs mature in alloSCT. Relevance: The deleterious effect of immune cells of the donor limits the application of hematopoietic stem cell transplantation in treatment of cancer and inherited diseases such as sickle cell anemia. The goals of our studies are to understand how immune cells are activated to cause disease and to modulate this activation so as to improve the safety and efficacy of stem cell transplantation.

描述（由申请人提供）：同种异体干细胞移植（AlloSCT）是一种挽救血液学恶性肿瘤和遗传性疾病（例如镰状细胞贫血和thalassyalassia）的救生疗法。 Allosct移植物中的T细胞扮演两个关键作用：1）它们重建成人的T细胞免疫，由于胸腺涉及，他们不会发展大量的供体干细胞衍生的T细胞； 2）它们介导抗肿瘤作用。不幸的是，供体T细胞还会引起供体T细胞对受体组织的供体T细胞的攻击。因此，所有患者都会通过耗尽同种异体移植物的T细胞或损害T细胞功能的药物而接受GVHD预防。然而，GVHD和免疫抑制的感染并发症是同种症发病率的主要原因。专业抗原呈递细胞（APC）通过启动罕见的同种反应性T细胞启动同种免疫T细胞反应。几种特征将移植中的抗原表现与传染性模型中建立的范例区分开。首先，AlloSCT接收者是供体和主机APC的嵌合体。迄今为止，我们的工作集中在表征GVHD发病机理中供体和宿主APC的独特作用。其次，在传染模型中，树突状细胞（DC）子集的作用在移植模型中尚未得到很好的定义。针对他们减少GVHD的有效策略的制定取决于这一知识。第三，当前DC在自适应免疫中的模型，其中病原体衍生的与模式相关的分子模式受体的配体刺激未成熟的DC成熟并迁移到继发性淋巴结，在同种中可能不会适用，而在没有特定的感染性apc的情况下，所有特定的感染性apc均呈现Allo andoantigen and Alloatigantigen，并且均为Indcate dc m.ctimation dc m.ctimate dc m.在此提案中：1）使用缺乏DC或DC亚群，抗体和免疫毒素的新型转基因小鼠来定义GVHD中的关键APC亚群； 2）使用转基因和缺乏基因的小鼠来测试有关DCS在同种异体中如何成熟的假设。相关性：供体免疫细胞的有害作用限制了造血干细胞移植在癌症治疗和遗传性疾病（如镰状细胞贫血）中的应用。我们研究的目标是了解如何激活免疫细胞以引起疾病并调节这种激活，以提高干细胞移植的安全性和功效。