Dendritic Cell Subsets and Paths of Maturation in Graft-vs.-Host Disease (GVHD)

描述（由申请人提供）：异基因干细胞移植（alloSCT）是恶性血液病和遗传性疾病（如镰状细胞性贫血和地中海贫血）的一种挽救生命的疗法。异源SCT移植物中的T细胞发挥两个关键作用：1）它们在成人中重建T细胞免疫，这些成人由于胸腺退化而不产生大量供体干细胞衍生的T细胞; 2）它们介导免疫效应。不幸的是，供体T细胞也会引起移植物抗-宿主病（GVHD），供体T细胞对受体组织的攻击。因此，所有患者通过从同种异体移植物中耗尽T细胞或使用损害T细胞功能的试剂来接受GVHD预防。然而，GVHD和免疫抑制的感染并发症是alloSCT发病的主要原因。专职抗原呈递细胞（APC）通过引发罕见的同种异体反应性T细胞来启动同种异体免疫T细胞应答。几个特征将移植中的抗原呈递与感染模型中建立的范例区分开来。首先，alloSCT受体是供体和宿主APC嵌合的。迄今为止，我们的工作集中于表征供体和宿主APC在GVHD发病机制中的不同作用。其次，在感染模型中具有独特性质的树突状细胞（DC）亚群的作用在移植模型中尚未得到很好的定义。制定有效的策略，以减少GVHD取决于这方面的知识。第三，DC在适应性免疫中的当前模型，其中模式相关分子模式受体的病原体衍生配体刺激未成熟DC成熟并迁移到次级淋巴结，可能不适用于不存在特异性感染病原体的alloSCT，所有受体APC都呈递同种抗原，并且诱导DC成熟的信号是未知的。在本提案中，我们：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;和2）使用转基因和基因缺陷小鼠来测试关于DC如何在alloSCT中成熟的假设。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治疗癌症和遗传性疾病如镰状细胞性贫血中的应用。我们研究的目的是了解免疫细胞是如何被激活导致疾病的，并调节这种激活，以提高干细胞移植的安全性和有效性。

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.