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

描述（由申请人提供）：同种异体干细胞移植（Allogeneic stem cell transplantation, alloSCT）是血液恶性肿瘤和遗传性疾病（如镰状细胞性贫血和地中海贫血）的救命疗法。同种异体干细胞移植中的T细胞起着两个关键作用：1)它们在成人中重建T细胞免疫，由于胸腺退化，不能产生大量供体干细胞衍生的T细胞；2)它们介导抗肿瘤作用。不幸的是，供体T细胞也会引起Graft-vs。-宿主病（GVHD），供体T细胞攻击受体组织。因此，所有患者都可以通过清除同种异体移植物中的T细胞或使用损害T细胞功能的药物来预防GVHD。然而，GVHD和免疫抑制的感染性并发症是同种异体细胞移植发病率的主要原因。专业抗原呈递细胞（APCs）通过启动稀有的同种异体反应性T细胞来启动同种异体免疫T细胞反应。有几个特征区分了移植中的抗原呈递与感染模型中建立的范式。首先，同种异体移植受体是供体和宿主apc嵌合的。迄今为止，我们的工作主要集中在表征供体和宿主apc在GVHD发病机制中的不同作用。其次，树突状细胞（DC）亚群在感染模型中具有不同的特性，但在移植模型中的作用尚未得到很好的定义。制定有效的战略以减少GVHD取决于这方面的知识。第三，目前适应性免疫中树突状细胞的模型，即模式相关分子模式受体的病原体衍生配体刺激未成熟的树突状细胞成熟并迁移到次级淋巴结，可能不适用于没有特异性感染性病原体、所有受体apc都存在同种异体抗原、诱导树突状细胞成熟的信号未知的同种异体细胞移植。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；2)使用转基因小鼠和基因缺陷小鼠来验证关于dc如何在同种异体干细胞移植中成熟的假设。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镰状细胞性贫血等遗传性疾病中的应用。我们的研究目标是了解免疫细胞如何被激活导致疾病，并调节这种激活，从而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.