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（alloSCT）是一种治疗血液恶性肿瘤和遗传性疾病（例如镰状细胞性贫血和地中海贫血）的挽救生命的疗法。 alloSCT 移植物中的 T 细胞发挥着两个关键作用：1）它们在成人中重建 T 细胞免疫，由于胸腺退化，不会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 细胞也会引起移植物抗宿主病 (GVHD)，即供体 T 细胞对受体组织的攻击。因此，所有患者都通过消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) 通过启动罕见的同种异体反应性 T 细胞来启动同种免疫 T 细胞反应。有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 的嵌合体。迄今为止，我们的工作重点是描述供体和宿主 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独特的特性，但在移植模型中尚未得到很好的定义。制定有效策略以减少 GVHD 取决于这些知识。第三，当前适应性免疫中DC的模型，其中模式相关分子模式受体的病原体衍生配体，刺激未成熟的DC成熟并迁移到二级淋巴结，可能不适用于没有特定传染性病原体的alloSCT，所有受体APC都呈现同种异体抗原和诱导DC成熟的信号未知。在这个提案中，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中关键的APC亚群； 2) 使用转基因和基因缺陷小鼠来测试有关 DC 在 alloSCT 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治疗癌症和镰状细胞性贫血等遗传性疾病中的应用。我们研究的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.