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

描述(申请人提供)：异基因干细胞移植(AllSCT)是治疗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。同种异体干细胞移植中的T细胞起着两个关键作用：1)它们重建成人的T细胞免疫，由于胸腺退化，不能产生大量的供体干细胞来源的T细胞；2)它们介导抗肿瘤效应。不幸的是，供者T细胞也会引起移植物抗宿主病(GVHD)，即供者T细胞对受体组织的攻击。因此，所有患者都接受GVHD的预防，要么通过耗尽同种异体移植物中的T细胞，要么使用损害T细胞功能的药物。然而，移植物抗宿主病和免疫抑制的感染性并发症是异基因干细胞移植发病率的主要原因。专业抗原提呈细胞(APC)通过激活稀有的同种异体反应性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，异基因干细胞移植的受者对于供体和宿主的APC是嵌合的。到目前为止，我们的工作集中在确定供体和宿主APC在GVHD发病机制中的不同角色。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很好地确定。以此为目标制定有效的战略以减少GVHD取决于这一知识。第三，目前的DC获得性免疫模型，即病原体衍生的模式相关分子模式受体的配体，刺激未成熟的DC成熟并迁移到次级淋巴结，可能不适用于没有特定感染病原体的同种异体SCT，所有受体APC都呈现同种异体抗原，诱导DC成熟的信号未知。在这项建议中，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；以及2)使用转基因和基因缺陷小鼠来测试关于DC如何在异基因SCT中成熟的假说。相关性：捐献者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。我们研究的目标是了解免疫细胞是如何被激活而致病的，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.