Dendritic Cell Subsets and Paths of Maturation in GVHD

异基因造血干细胞移植（alloSCT）是恶性血液病的救命疗法， 遗传性疾病，如镰状细胞性贫血和地中海贫血。异基因造血干细胞移植中的T细胞起着两个关键作用 作用：1）它们重建成人的T细胞免疫，由于胸腺退化， 供体干细胞衍生的T细胞的数量;和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细胞对受体的攻击 组织中因此，所有患者都通过从同种异体移植物中耗尽T细胞或 用的是损害T细胞功能的药物尽管如此，GVHD和感染并发症， 免疫抑制是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。若干特征 区别移植中的抗原呈递。首先，alloSCT受体是供体和宿主嵌合的 装甲运兵车迄今为止，我们的工作集中于描述供体和宿主APC在GVHD中的不同作用 发病机制第二，DC包含具有重叠但不同性质的一组不同的细胞， 这些DC亚群的作用在移植模型中没有很好的定义。第三，也许是大多数。 对于本申请重要的是，目前DC在适应性免疫中的范例，其中病原体来源的 模式相关分子模式受体（特别是Toll样受体）的配体， 刺激未成熟DC成熟并迁移到次级淋巴结，可能不适用于alloSCT， 没有特异性的感染性病原体，诱导DC成熟的信号也是未知的。在这 我们计划使用试剂和基因缺陷小鼠的组合来定义关键的APC亚群， GVHD，它们的成熟途径，并将测试它们的调节可以改变同种免疫的假设 来获得治疗效果

Allogeneic stem cell transplantation (alloSCT) is 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. 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, DCs comprise a diverse set of cells with overlapping but distinct properties and the roles for these DC subsets are not well defined in transplantation models. Third and perhaps most important to the present application, the current paradigm for DCs in adaptive immunity, in which pathogenderived ligands for pattern associated molecular pattern receptors (in particular Toll-like receptors), stimulate immature DCs to mature and migrate to secondary lymph nodes, may not apply in alloSCT where there are no specific infectious pathogens and signals that induce DC maturation are unknown. In this proposal we plan to use a combination of reagents and gene deficient mice to define critical APC subsets in GVHD, their pathways of maturation, and will test the hypothesis that their modulation can alter alloimmunity for a therapeutic gain.